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7Year

 

by Monica Coenraads

Today is the seven-year anniversary of the launch of RSRT. In the midst of crazy schedules and workloads, anniversaries offer an opportunity for a few quiet moments of reflection on both achievements and challenges ahead.

For me the last 7 years, while demanding, have been the most rewarding of my life. To be given the freedom, the confidence and the trust by my board, our donors and the families that raise funds to pursue the work that will one day free our girls, my precious Chelsea included, is a gift that I cherish.

While science can never move fast enough to satisfy my maternally inspired timeline for a cure, I recognize that the Rett research field has come a very long way in the past 7 years. And it’s satisfying to know that RSRT has had more than a tad to do with this progress.

From the get-go RSRT was committed to funding people and projects with the potential to dramatically change the lives of our girls. Settling for marginal improvements is simply not good enough.

An exciting area of research, activating the silent MECP2 on the inactive X chromosome, was put on the research map by RSRT. It wasn’t easy as scientists were skeptical and hesitant. We started by funding one lab, then two, then another joined. Today we are supporting six labs that are trying synergistic approaches to waking up the back up MECP2 gene. These scientists have bucked the traditional “we work alone” mentality that plagues science and are showing remarkable openness and trust as they share their data, brainstorm and troubleshoot, via in-person meetings and conference calls.

Industry is showing interest in this approach due to the advantages that it brings: the approach addresses the root of the problem, you don’t have to deliver MECP2….it’s already there; no worries of having too much MECP2; the approach would be pharmacological (a drug) rather than biological (gene/protein therapy).

Another approach that has been put on the map by RSRT is the hunt for modifier genes that dampen the ill effects of an MECP2 mutation. The first modifier, squalene epoxidase, was published in 2013 by Monica Justice and has led to a clinical trial currently ongoing at Children’s Hospital at Montefiore in the Bronx.

The screen is now just over halfway through and Dr. Justice has identified several dozen modifiers. Interestingly, the modifiers are not ad hoc all over the genome but rather are falling within distinct molecular pathways. By the time the screen is done we may have 50 or so modifiers some of which will undoubtedly be druggable. Dr. Justice’s data has also revealed that Rett Syndrome has characteristics of metabolic disease, something that had not been fully appreciated before.

Rett is a complex problem and no single lab has the expertise and resources to eradicate it. So early on RSRT cultivated an environment where collaborations could flourish. While such partnerships cannot be imposed, they can be nurtured and RSRT has done just that with our MECP2 Consortium, which launched in 2011 and our Gene Therapy Consortium that started two years later. Scientists who were previously competing are now working together to solve difficult problems.

The most dramatic evidence that our science is maturing and that progress is being made is the interest in Rett from pharmaceutical and biotech companies. I’m sometimes tempted to pinch myself to make sure I’m awake and not dreaming. Scientists studying many other diseases including autism would give their right arms to be where we are at this very moment.

Along the way I’ve learned a few valuable lessons:

  1. Do not fall in love with the science that we fund. To do that means to lose objectivity.
  2. Stay nimble – new technologies and data must continually be monitored for and adopted when appropriate.
  3. Don’t become insulated – RSRT is constantly soliciting feedback on “everything Rett “– every paper that comes out and every announcement that is made receives a thorough objective and comprehensive analysis
  4. Don’t accept dogma without proof
  5. Surround yourself with smart and creative people – mediocrity won’t cut it

While it’s healthy and necessary from time to time to step back and recognize our achievements, the time to celebrate has not yet arrived. That time will come when our girls are healed and can celebrate with us.

For now there are challenges ahead and lots of work still to be done. Speaking of which…. back to the real work at hand for me.

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I often come across statements to this effect, “The pharmaceutical industry is not interested in pursuing drug development for Rett Syndrome because the disorder is rare and companies won’t make any money.”

And yet, I am fielding emails, calls and in-person meetings with industry executives almost on a daily basis. From my perspective, Rett is clearly on the industry’s collective radar. This goes for both large pharmaceutical companies and smaller biotech firms, but why?

Industry is flocking to rare diseases and here are some of the reasons why:

  1. The biology of rare diseases is often better understood than that of common diseases. This is certainly the case with Rett because it is caused by a mutation in a single gene that has already been pinpointed.
  2. The US Orphan Drug Act, created to facilitate the development of drugs for rare diseases, provides companies with tax credits, funding grants for clinical trials, a waiver of FDA fees and 7-year market exclusivity.
  3. Rare disease drugs can demand hefty price tags. Annual costs of $100K to $500K are not unusual.
  4. Rare disease drugs have reduced marketing costs and often increased reimbursement possibilities.
  5. Clinical trials are much smaller therefore cheaper, and enthusiastic patient population often makes for easier trial recruitment.
  6. Drugs designed to treat rare disorders sometimes prove to be beneficial for a broader patient group.

Companies like Genzyme, Shire, Vertex, Alexion, BioMarin, Celgene and Aegerion just to name a few, have firmly established a successful business model for rare disease drug development.

This paradigm shift is good news for Rett. In addition to the above perks Rett offers a unique advantage that has not gone unnoticed by industry executives: reversibility!

While it’s extremely gratifying to witness this activity we must not let up on the intensity with which we support and drive basic science and clinical research. Industry’s interest in the therapeutic approaches that RSRT has been pursuing (activating the silent MECP2, modifier genes, downstream targets such as NMDA pathways, gene therapy) validates our research strategy. Our research has fueled a rich pipeline of potential drug targets and it’s imperative to keep that pipeline flowing.

 

We’re delighted to share this monumental honor with the Rett community. Our very own Monica Coenraads was awarded an honorary doctoral degree from UMass Medical School at their 2015 commencement ceremonies. It goes without saying that Monica’s knowledge, passion and courage provide not only the backbone but the spirit of our organization. We could think of nobody more deserving than Monica. 

The chancellor put it best “A diagnosis that would have been an emotional setback for others, instead set the stage for your emergence as a central figure in one of the most successful advocacy stories in modern medicine.” She is truly a pioneer and our fiercest warrior leading the charge in the war on Rett.

This is a great honor not only for Monica but also for RSRT.  It’s a testament to the respect she and the organization have in the scientific and medical community.  It’s also further testament to why all of us Rett parents are fortunate that Monica does what she does.

 -Tony Schoener, Chair, RSRT Board of Trustees

For a variety of reasons the pharmaceutical industry over the last few years has become more and more interested in rare disease. This is great news for Rett Syndrome.  As terms like orphan drug designation, breakthrough therapy, efficacy, drug approval, market exclusivity become part of our everyday lingo it is important that our understanding of them is based in facts. As we start the process of learning and sharing information we bring you this interview with regulatory consultant and Former Director of the FDA Office of Orphan Product Development, Timothy Coté.

by Monica Coenraads

As always at RSRT, our funded projects are aimed at developing effective treatments and a cure for Rett Syndrome. But one of the key roadblocks to achieving this has been a lack of knowledge about the MeCP2 protein and how it functions. In 2011 RSRT decided to conduct an experiment of our own. Take three world-class laboratories and give them the necessary financial resources ($5.5 million awarded to date) and infrastructure to tackle a question that no one yet has been able to answer: what does the MeCP2 protein do?

Almost four years later the labs of Gail Mandel (Oregon Health and Science University), Michael Greenberg (Harvard University), and Adrian Bird (University of Edinburgh) are getting closer to that answer and have made the following discoveries along the way— discoveries that could prove to be invaluable to how we will ultimately change the lives of girls and women afflicted with Rett:

  • It was known that MeCP2 binds to DNA in brain cells, but the Consortium showed that MeCP2 has a binding partner, called NCOR, that is known to silence genes. Importantly, the Consortium showed that mutations that disrupt the ability of MeCP2 to bind to NCOR are associated with Rett in people, thus lending support for the essential nature of this interaction.
  • MeCP2 is modulated by phosphorylation for normal nervous system function.
  • The Consortium has shown that gene therapy can reverse symptoms in symptomatic female Rett mice. This work is being actively followed up by a dedicated “Gene Therapy Consortium” also funded by RSRT.
  • As yet unpublished work is shedding light on the crucial question of which genes in the brain are controlled by MeCP2. It may be possible to target these genes via specific drugs.
The MECP2 Consortium meets in Boston twice a year and holds conference calls in between the meetings. The meetings at first included only Professors Mandel, Bird and Greenberg but have grown over time to include many of the lab members. The middle and right pictures are from the last meeting in October 2014.

The MECP2 Consortium meets in Boston twice a year and holds conference calls in between the meetings. The meetings at first included only Professors Mandel, Bird and Greenberg but have grown over time to include many of the lab members. The middle and right pictures are from the last meeting in October 2014.

Recently I posed a few questions to the three investigators about the important work they are tackling.

Why is uncovering the function of MeCP2 important?

adrian-birdDespite much effort, there is little consensus among scientists regarding what MeCP2 actually does in the brain. Needless to say it helps greatly when fixing something to know exactly what has gone wrong, so this is an issue that badly needs addressing. Fortunately the research tools for getting at the problem have gotten much better over the past few years and we are now in a good position to nail this problem down.

gailIt’s important to know why the loss of MeCP2 gives rise to Rett as well as helping to determine a minimally active form that might be better suited to gene replacement approaches.

Is it necessary to know the function of MeCP2 to discover treatments?

greenIt is hard for me to imagine a treatment for Rett that isn’t based on an understanding of MeCP2 function. Based on what we already know about MeCP2 it is clear that it’s function in neurons is quite complex and difficult to understand. That together with the complexity of the brain makes me think it is unlikely that a therapy that isn’t based on a deep understanding of MeCP2 function is likely to work. Nevertheless, I wouldn’t rule it out.

adrian-birdIf we could correct the genetic changes that cause MeCP2 to dysfunction in Rett so that the defective gene is replaced by a healthy one, then we would not need to know how MeCP2 works. This ideal scenario is becoming less of a fantasy, but is still some ways from being a reality. Knowing precisely what pathways MeCP2 regulates offers the prospect of treating downstream effects of the mutation as an alternative to correcting the gene. It is too early to say at the moment which approach is more likely to bear fruit so it is important to try both.

How has being part of the Consortium impacted your lab’s research?

gailI think investigators in other disciplines would love to have what we have built together. The Consortium is a wonderful stimulus for new ways of thinking critically about how to study and/or cure Rett. Two heads, or in this case three heads, are always better than one, particularly because we have different expertise and backgrounds. And we can build on each other’s discoveries much more quickly.

adrian-birdThe Consortium is a new way of working that has benefited our lab’s work greatly. Being able to thrash out ideas and explore different ways of looking at Rett with top class scientists from different backgrounds has sharpened up everybody’s research. All the partners have fully committed to the Consortium idea and as a result no one feels inhibited about robustly questioning the others. This kind of free and frank exchange keeps us on our toes and always makes research better. As well as ideas and data, we share materials and equipment, which speeds up our work and reduces costs.

How would you describe the experience of working collaboratively? Has anything surprised you?

adrian-birdScience is usually built on a competitive model where PIs compete for funding and try to make and publish discoveries ahead of their peers. Sharing data and plans for experiments with people who were once competitors is a different way of working – but one that is also liberating. It requires trust and a recognition by everyone that a higher goal is at stake. This Consortium really works. Hopefully we are poised to advance our knowledge of MeCP2 in ways that will make a difference therapeutically.

gailIt has been very rewarding. Nothing really has surprised me because I knew Adrian Bird and Mike Greenberg pretty well beforehand and I had ultimate confidence in the high quality of their science and their collegiality.
 

 

 

Participating in the Consortium and working collaboratively with the Mandgreenel and Bird labs has been a wonderful experience. The rigor and pace of scientific progress is much greater with the three labs working together than would be possible if each lab were working alone. Monica has been essential to keeping the Consortium on target and helping make sure the scientists in the Consortium continue to work together effectively over time.

The lab members from the three labs have thoughts of their own about the MECP2 Consortium.

Consortium Research Projects Reflections on Meeting
Harrison Gabel
(Greenberg lab)
gabel
Benyam Kinde, Caitlin Gilbert, William Renthal and myself have been studying how MECP2 functions when it is bound to DNA in neurons and how it might control the levels of many proteins important for the function of neurons in the brain. This exciting work may provide an answer to the long-standing question of exactly what goes wrong in individual neurons in the Rett Syndrome brain when MeCP2 is lost. I described recent results from experiments using cultured mouse neurons that lack MeCP2 to test whether drugs can correct the defects in these neurons. Promising results from these experiments suggest that a drug can at least partially correct these defects. We are now beginning to explore if this drug can improve symptoms in mice with Rett Syndrome by delivering the drug to the brain of these mice. In general it is truly unprecedented to have three powerhouse labs that work on the mechanism of MeCP2 get together for a meeting and share their most recent data. The reality is that under any other circumstances we would be competing (hopefully in a congenial way!) and largely keeping secrets from one another until the data were published. This Consortium breaks down these walls and as a result the science moves much faster. I commend Adrian, Gail, and Mike for being willing to share so much, all of the lab members for trusting in the other Consortium members to treat them fairly, and most of all RSRT for creating such a unique and effective Consortium. Thanks!
Benyam Kinde
(Greenberg lab)
At the meeting I spoke about experiments that provide insight into the mechanism of MeCP2-mediated gene regulation. Through a series of biochemical, genetic and genomic experiments, I described how DNA methylation, specifically occurring in the CA dinucleotide sequence context in neurons, serves as a critical site for MeCP2 binding and regulation of gene expression in the developing brain. The Consortium has provided a unique opportunity to share novel findings, which ultimately has led to invaluable discussions that provide critical insight into the design and interpretation of experiments. In this way, the Consortium has allowed all three laboratories to develop projects at an exceedingly rapid pace.
Matt Lyst
(Greenberg lab)
Last year we published evidence for a model where the primary function of MeCP2 is to recruit the NCoR/SMRT co-repressor complex to chromatin.
At the last Consortium meeting I presented work aimed at further testing this hypothesis, and also investigating which components of this complex are most relevant to Rett Syndrome.
Sharing current data between labs means we all receive input from people in the field but outside of our own labs at a much earlier stage than would normally happen.
Sabine Lagger
(Bird lab)
MeCP2 is classically described as a methyl DNA binding protein exerting its function by exclusively binding to methylated CpG dinucleotides. It became obvious in recent years that MeCP2 can not only bind to methyl CpG dinucleotides but has been suggested to bind to other forms of modified DNA in in vitro experiments broadening its DNA binding sites. My work aims at establishing in vivo models to analyze MeCP2 binding patterns in brain cells. I therefore sort neuronal and glial cells from mouse brain and subject them to DNA methylation analysis to the single base pair resolution level. I can then overlay these maps with MECP2 binding profiles and identify the true in vivo MeCP2 targets. This analysis will help us to understand how MeCP2 is acting on chromatin and what the necessary signal for its binding are. I was invited to the RSRT Consortium meetings in Boston twice and both times I could not wait to get back to the lab and start working again. The possibility to present and discuss my work with like- minded and enthusiastic experts on MeCP2 is extremely beneficial and made me look at scientific problems from different angles. Meeting Rett Syndrome patients’ parents was very interesting for me and made me realize even more how important it is to keep working on understanding this devastating disease and to ultimately find a cure.
John Connelly
(Bird lab)
The MeCP2 protein acts by interacting with DNA at many locations inside cells. It is not clear however exactly what DNA sequences MeCP2 binds to on chromosomes. My work aims to identify what these sequences are.
My hope is that understanding how the protein works in greater detail will aid the design of an effective therapeutic strategy.
I was really pleased to be able to attend the recent MeCP2 Consortium meeting in Boston as it was really nice to meet and talk to the parents of children with Rett syndrome and discuss my work with them and the other scientists present. When in Boston I found that other members of the Consortium had, reassuringly, reached similar conclusions and this gave me the impetus to continue my particular avenue of investigation.
Hume Akahori-Stroud
(Greenberg lab)
I talked about a series of experiments on understanding the role of DNA methylation patterning in the brain. DNA methylation is a chemical modification of DNA that is abundant in neurons, and regulates MeCP2 function. Understanding the molecular mechanisms of DNA methylation in regulating MeCP2 is important to understand how MeCP2 works. It was great getting to know what other laboratories were up to, and I think the meeting has increased my understanding on MeCP2 a step further.
John Sinnamon
(Mandel lab)
Many of the mutations in MeCP2, which cause Rett Syndrome are single nucleotide changes known as point mutations. Our goal is to harness the catalytic activity of an enzyme already found in cells to target and correct these mutations in MeCP2 RNA. We have been able to edit MeCP2 RNA in vitro and are working towards testing our strategy in a mouse containing a point mutation, which has been identified in several Rett patients. Attending the RSRT Consortium meetings is a wonderful experience. There is a collaborative atmosphere you do not see at large scientific meetings and everyone is focused on understanding the biology of MeCP2 so that we can understand Rett Syndrome. For me personally, it is very powerful to meet parents of girls with Rett and to talk to them about my research. It provides a reminder of what I am working towards and I think gives the families an opportunity to talk one on one with the scientists they support.
Ruth Shah
(Bird lab)
My project involves modeling Rett – causing mutations in human neurons. Model systems are a great way to elucidate the molecular mechanisms behind diseases and to understand how a protein works in a cellular context. I really hope these human neurons will help us to understand the details involved in Rett, they may even provide a useful tool for testing gene therapy ideas in! Being part of the Consortium meeting gave me the opportunity to meet neuroscientists and gain advice and ideas from them on how to improve my project and my research. The flexibility to present my project in detail to an experienced audience without fear of my project being torn apart is a great thing. It provides the freedom for open chat and encouragement and an exchange of thoughts and ideas in a positive manner, rather than having a competitive undertone to the day. This is the environment that is needed in scientific research to encourage advances in knowledge. It allows for collaboration in a productive manner, for example as a result of the Consortium, I now have a list of genes whose expression I should look into from one of the other attending labs. If it weren’t for the Consortium I doubt information like this would be shared among labs in such an open manner.
Jackie Guy
(Bird lab)
Using information we have about the MECP2 mutations found in girls with Rett we have been able to identify two important regions of the protein: the region that binds to methylated DNA (MBD) and a small region which binds to a repressor complex, NCoR/SMRT. I am producing a number of different mutations in mouse embryonic stem cells in order to investigate why they cause Rett Syndrome. This may lead to a better understanding of the function and/or structure of MeCP2. I enjoyed hearing about the work of the other two groups in the Consortium. Each group has its own particular view of what MeCP2 is doing and I found it refreshing to think about things from a slightly different angle.
Rebekah Tillotson
(Bird lab)
Missense mutations that cause Rett are almost all located in either the region of MeCP2 protein that binds to methylated DNA or the region that interacts with the NCoR/SMRT repressor complex. This suggests that the function of MeCP2 is to form a ‘bridge’ between chromatin and the repressor proteins, and loss of this bridge results in brain dysfunction in Rett. I am testing this hypothesis by manipulating the MeCP2 gene in mice, and then carrying out behavioral tests to determine whether they exhibit the symptoms observed in the mouse models of Rett. The RSRT Consortium was a great opportunity for me to meet other scientists in the field, to learn about and discuss their work, and to get valuable input on my own project. The informality and openness of the discussion made it a thoroughly rewarding and stimulating experience.
Kyla Brown
(Bird lab)
Rett Syndrome severity varies partly because of the nature of the MECP2 mutation. My project focuses on making animal models of “milder” mutations to see if there are specific functions of MeCP2 that these mutations affect. The Consortium provides a unique opportunity to communicate findings within a group of expert researchers as well as to forge collaborations. I enjoyed being able to appreciate others’ perspectives on the same clinical and biological problem and seeing how this can result in advances in the MeCP2 field.
Martha Koerner
(Bird lab)
I am working on MeCP2 duplication syndrome. I am trying to understand what happens if you do have too much MeCP2 and what we can do to counteract the symptoms caused by excess MeCP2. The Consortium meeting in October was the first one I’ve attended. I’ve found it incredibly helpful to be able to talk to other scientists who work on the same gene, to learn about novel findings of others that will impact my research and also to get input from experts into the work I’m doing.
Susan Su
(Greenberg lab)
I am interested in examining the ultrastructural changes underlying the altered cellular morphology and synaptic connections of a mouse model of Rett Syndrome. I enjoy our lively, intellectual discussions at the Consortium meetings where we all share a common goal of gaining a deeper understanding of MeCP2. The Consortium meetings are wonderful opportunities to reflect on preliminary data and to share helpful reagents and insights for our experiments.
Jim Selfridge
(Bird lab)
My work in the Bird Lab focuses on the production and analyses of genetically modified animal models of Rett. These models have proved invaluable to Rett research over the years and the novel models continue to increase our understanding of MeCP2 function and the underlying molecular basis of Rett. I am also committed to using these Rett models to investigate potential therapeutic strategies. Although I never actually presented any of my research in person at the last meeting I was still able to benefit hugely by attending. The Consortium meetings and in particular the relaxed, open and friendly format provide a great focus for Rett researchers. It gives us a perfect opportunity to have our work critically assessed by experts in the field, even in the early stages of a project. This often affords us extra insight that we might not get from the sometimes insular environment of our own individual groups.
I look forward to being part of many more meetings!
Will Renthal
(Greenberg lab)
Rett is characterized by profound synaptic dysfunction. I am studying the role MeCP2 plays in coordinating the gene programs responsible for normal synaptic responses to neuronal activity. Specifically, our laboratory has found that neuronal activity drives the rapid phosphorylation of MeCP2 at serine 86, so my current efforts are aimed at identifying the functional significance of this event. I think the Consortium was a fantastic opportunity to share ideas with people from a variety of backgrounds to accelerate Rett research. We were having technical difficulties with some of our experiments and the collective wisdom of the Consortium has been crucial for overcoming them.
Justyna Cholewa-Waclaw
(Bird lab)
The aim of my project is to define primary transcriptional consequences of MeCP2 depletion. In order to do that I use an in vitro system based on immortalized human neural precursors which can be differentiated into dopaminergic neurons. I generated cells with reduced amount of MeCP2, entirely depleted MeCP2 and increased levels of MeCP2. Gene expression changes in these cells with different levels of MeCP2 will be studied additionally in the context of gene body methylation and hydroxymethylation to provide the molecular basis of MeCP2 function. I think the Consortium meetings are great.  The informal nature is very beneficial. I had brilliant opportunity to discuss my work with people working on the same problem. I could also ask questions more openly and know what other people are doing.

by Monica Coenraads

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This past November the Cystic Fibrosis Foundation (CFF) announced an unprecedented windfall: $3.3 billion from selling royalty rights to drugs that it helped develop to treat Cystic Fibrosis. The payout is the largest financial return ever secured by a disease non profit. The CFF is the gold standard for anyone working in the disease non profit world.

Years ago I had the good fortune to meet the founder of CFF, Doris Tulcin. She now serves on our Professional Advisory Council.  I consider myself lucky to count Doris as well as the CFF CEO, Bob Beall, among my mentors. Their $150 million investment for this particular drug has paid off handsomely and I couldn’t be happier for them and for the entire CF community. It’s been interesting however to see the spectrum of opinions regarding this windfall. Below are two polar opposite commentaries on the subject.  I encourage you to read them both.

In case you are wondering whose view I agree with…it’s Peter Kolchinsky!

Rethinking Venture Philanthropy After the Kalydeco Windfall
by Peter Kolchinsky

KolchinskyThe Cystic Fibrosis (CF) Foundation’s big win in venture philanthropy can fuel constructive competition among companies developing innovative CF drugs, benefiting both patients and the healthcare system by increasing future treatment options and reducing their cost.

CF is a fatal genetic disease affecting around 30,000 people in the U.S. that is caused by mutations in the cystic fibrosis transmembrane receptor (CFTR) gene. These mutations disrupt either the expression or function of the CFTR protein, causing mucus buildup in the lungs that can impair breathing and lead to infection. Although the most severe symptoms of CF impact the lungs, the disease also leads to a shortage of the pancreatic enzymes needed for digestion.

The vast majority of drugs marketed to treat CF address the symptoms, and not the cause of the disease. Ivacaftor (Kalydeco), a drug from Vertex Pharmaceuticals (NASDAQ: VRTX) that was developed with an investment from the CF Foundation, is the only therapy available that addresses the underlying cause of CF, though currently only for a small fraction of patients with particular mutations. Vertex is developing other drugs, so-called CFTR correctors, that can be combined with ivacaftor to address more CF patients.

Royalty Pharma’s $3.3 billion purchase of the CF Foundation’s roughly 10 percent royalty on Vertex’s CF drugs last month sparked some controversy. Articles in the New York Times and Xconomy suggested that the foundation had somehow failed patients by allowing Vertex to price its drugs so high that a 10 percent royalty could be worth so much. These criticisms echo those directed at the foundation when ivacaftor hit the market in 2012.

Ivacaftor’s price tag, about $300,000 per year, per patient, shocked the market. Critics declared that the CF Foundation should have done more to ensure an affordable price for patients. They further insinuated that the drug’s price was evidence that the foundation had a conflict of interest; it could not simultaneously serve patients and fund biotech companies. In the wake of the multibillion-dollar royalty sale, critics are now repeating these same accusations.

These critics are missing an important part of the CF Foundation’s strategy. While the foundation could not possibly have any leverage over how Vertex priced its drug, by harvesting $3.3 billion now, it will be able to speed the development of over a dozen early competitors. This will usher in an era of competition that will help make the CF therapies of the near future not only better, but also less expensive—long before Vertex’s drugs go generic.

Read more

Stop Subsidizing Big Pharma
by Llewellyn Hinkes-Jones

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Robert J. Beall, the president and chief executive of the Cystic Fibrosis Foundation, called his recent decision to sell the royalty rights to his organization’s research a “game changer.” Indeed: Deals like this, in which an investment company paid the foundation $3.3 billion for its future royalties from several cystic fibrosis drugs it helped finance, could revolutionize the way medical research is funded. Rather than the staid model of government-funded institutions handing out grants to academic research facilities, a new breed of “venture philanthropies” like the Cystic Fibrosis Foundation could corral private investment into developing lifesaving drugs quickly and cheaply.

The problem is that venture philanthropy is, essentially, another term for privatizing scientific research. Instead of decisions about the fate of scientific funding being made by publicly oriented institutions, those decisions are being put in the hands of anonymous philanthropists and ostensibly benevolent nonprofits.

At the risk of oversimplification, biomedical research divides into two categories: private and public. The former is the constellation of big pharmaceutical companies and start-up labs. The latter comprises government agencies and the universities and philanthropies that rely on government support — directly, through grants, or indirectly, through tax policy. The former can charge whatever it wants for its products; the latter is limited by government rules and price controls.

Venture philanthropy complicates this picture by introducing a tax-exempt loophole. An organization like the Cystic Fibrosis Foundation will take in tax-exempt donations to invest in a pharmaceutical company — in this case, Vertex Pharmaceuticals — to develop drugs based on publicly funded research. Venture philanthropies can then sell the results of that research to private industry to deliver drugs to the market.

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So many of our kids suffer from gut problems – constipation, reflux, bloating and pain. Despite the prevalence of GI issues in Rett this is an area that has been mostly unexplored by scientists. So we are happy to add Dr. Ali Khoshnan of Caltech to our growing list of funded researchers. Dr. Khoshan will be exploring the gut physiology of mice models of Rett. He will also be testing a powerful probiotic (not currently available for people) in the mice to see if any Rett symptoms improve. Watch the video below to learn how the study of the microbiome (the community of microorganisms that populate us and outnumber our cells 10:1) has become a very hot field in science and how it might be applied to Rett Syndrome.

by Monica Coenraads

Chelsea is 18 years old today. It’s a milestone birthday that parents of special needs children face with mixed emotions. My heart is full with love and pride for the beautiful, emotive, tender yet determined young woman that Chelsea has become. But today I am also mourning. Mourning for a childhood never lived and forever lost.

Chelsea beach

When Chelsea was a toddler I made her a promise – that I would do everything in my power to heal her. With little science background, zero drug development knowledge and no fundraising experience I did not appreciate the enormity of my promise. Ignorance, at times, can be a blessing.

The Rett research landscape in the year Chelsea was diagnosed, 1998, was dismal. The disorder was practically unknown in medical and scientific circles, there was no known gene and therefore no diagnostic blood test, there were no animal models, and there was little research beyond trying to pinpoint the genetic cause.

My conviction that treatments and a cure for Rett were possible came from both visceral intuition and a mother’s love. Today that conviction is based on science.

But when will that cure come? Is it really “around the corner” as I so often read on facebook and other social media? I do not know the timeframe associated with “around the corner” (is it weeks, months, years?) but I am confident that a number of treatments will become available to our children in the coming years that will improve certain symptoms. The Potential Rett Syndrome Therapeutics chart on the RSRT website provides insight into the numerous interventions currently being pursued.

As parents we will take any improvement in our children’s symptoms that we can get. But what about the “like it never even happened” cure? (My all-time favorite catchphrase from the disaster restoration company, SERVPRO) For now we do not know whether the cure will be gene therapy, or protein replacement or activating the silent MECP2 (or the entire X chromosome) or a drug that modulates a modifier gene or perhaps a combination of some or all of these approaches. And we don’t know what a cure for someone like my daughter, who is now an adult, will look like. Will she be able to speak, to walk, to use her hands?

I do not focus on these questions because they are, for now, unanswerable. I concentrate only on the facts and these include:

  • The reversal experiments originally done in Adrian Bird’s lab and repeated over and over again in many labs gives us solid proof-of-principle that dramatic reversal of symptoms should be possible. I have yet to hear one piece of scientific data that would dampen my optimism that a cure is possible.
  • Scientists are making progress on many fronts including gene therapy.
  • Rett researchers are collaborating and sharing information in real-time in a way that is unprecedented. Examples include the MECP2 Consortium, the Gene Therapy Consortium, and researchers focused on reactivating the silent MECP2.
  • Technologies exist today that are enabling experiments that only a few years ago would be impossible.
  • Rett has become a high-profile disorder in scientific circles.
  • Biotech and big pharma, for the first time, are showing an interest in Rett Syndrome.
  • Science is not linear. We do not know what might lie around the corner that can dramatically accelerate the development of a cure.

Those of you who know me will know that I am aggressive when it comes to pushing the science forward but I am conservative in how research progress is relayed to families. I prefer facts over hype.

Could a cure for Rett be around the corner?  The answer to that question will come when we have a clearer picture of what form that cure will take.  I can assure you that I will not rest until we accomplish that.

Love alone cannot cure Rett but love and research will. It’s been 16 years and I am more than ready to deliver on my promise.

Monica Coenraads interviews Michael Green, MD, PhD of the UMASS School of Medicine about his newly published paper in Proceedings of the National Academy of Sciences.  The work was funded, in part, by RSRT.  He has identified a number of genes that when disrupted can reactivate the silenced X chromosome in females. Some of these genes lie in pathways that are druggable which makes this work potentially clinically relevant not only for Rett Syndrome but also for other X-linked disorders.

Prof. Green’s paper was covered by SFARI.org. in an article written by Jessica Wright.


Rousing silenced X chromosome may treat Rett syndrome

Drugs that activate the silent copy of the X chromosome in women may be able to undo the damage from mutations in genes located there. The study, published 2 September in Proceedings of the National Academy of Sciences, offers hope for treating Rett syndrome and other disorders linked to the chromosome1.

One copy of the two X chromosomes women carry is randomly silenced in each cell of the body. This occurs when the chromosome makes small pieces of RNA, called X-inactive specific transcript, or Xist. A cloud of Xist coats the chromosome and blocks its expression.

Female mice lacking Xist die in utero, so X inactivation was thought to be required for survival. The new study suggests otherwise.

The researchers identified 13 genes required for X inactivation. Female mice missing STC1, one of these genes, show expression of genes from both copies of X and have no obvious symptoms.

“The mouse findings suggest that you might be able to survive without X chromosome inactivation,” says lead researcher Michael Green, professor of molecular medicine at the University of Massachusetts Medical School.

Continue reading

by Monica Coenraads

Anyone who knows anything about Rett Syndrome knows that the disorder is primarily seen in girls. The disorder is caused by disruption of the MECP2 gene located on the X chromosome. Girls have two X chromosomes one with the disrupted gene and one with the healthy gene. Having some healthy MeCP2 protein allows girls to survive but at the expense of severe impairment that comes with Rett.

1623703_516732648427830_2098385048107441333_n

Since boys only have the one X chromosome they have no healthy MECP2 at all. These boys typically have a more severe form of the disease and often die in early childhood. (There are genetic situations that allow boys to present like classic girls with Rett, for example if they have Klinefelter Syndrome which gives them two Xs.)

The fact that boys only have one X is the reason most often given for why Rett is seen in girls. However this is not accurate. While having the sole X is the reason boys often succumb to the disease it is NOT the reason why Rett is primarily a woman’s disease. That reason has to do with where the MECP2 mutation originates.

Many studies over the past decade have provided evidence that the vast majority of MECP2 mutations originate in the sperm. Since fathers give an X to their daughters and a Y chromosome to their sons the MECP2 mutation can only be transmitted from father to daughter. This is the reason why Rett is seen primarily in girls.

y-chromosome

Boys, on the other hand, get their MECP2 mutations from their mother, a situation that arises only rarely. (Mutations can also originate in a single cell as the male embryo is developing.)

Scientific papers over the years have hypothesized that because male fetuses only have one X their disease would be so severe that they might not even develop to full term and the mothers might miscarry. There is no clinical data to support this hypothesis whatsoever.

Due to the sheer volume of sperm that is continuously made it is likely that all men produce sperm with MECP2 mutations. One in about 20,000 eggs will be fertilized with a sperm that has an MECP2 mutation in it – the cruel reality of genetic roulette.

Dear Friends,

Tim and his daughter Eleanor

Tim and his daughter Eleanor

A year ago today I started as program director for RSRT.  I thought I would share a few reflections about the people I’ve met and what I’ve experienced and learned over that time.

Before starting at RSRT I had met two girls with Rett Syndrome—my own daughter and Monica’s daughter.  Now, in my travels to events and meetings with families, I have met 47 girls and young women with Rett.  Each of them, often despite terrible symptoms, has tried to engage me in some way, sometimes just through a flash of the eye or a smile.  I met a teenage girl at an event who had been seizure-free for six months.  But midway through the event she had a seizure.  I watched as she trembled and her muscles seized; a single tear rolled down her cheek.  Was it pain, frustration, fear?  It was so clearly all of those.  Her father and mother cried too.  So did I.  Of all I have learned and experienced over the last year, nothing sticks in my memory or keeps me awake at night like the faces of these girls and women and the strength I have seen in them and in their families.  Our daughters have reminded me again and again without saying any words that it’s imperative that we change their lives.

MacDonald Family at this year’s Quest for a Cure

Tim and MacDonald family at the
Quest for a Cure event

I have also learned that it’s we—the families of girls and women with Rett—who are going to make this happen. We are the leaders in this cause. I’m not at all suggesting that we families have to throw money at this. I am well aware that we all have plenty on our plates; we have to live our lives, and the daily challenges of Rett Syndrome add emotional and financial stresses that most people don’t even have to think about. So we can’t be expected to shoulder the full burden of supporting Rett research on top of everything else. But, we all can make a critical difference by getting friends and contacts to support RSRT. Thanks to the efforts and outreach of some Rett families, many people who are not directly affected by Rett have generously and happily supported the research and have made it a priority for their giving. We, all of us families, have to continue and expand this outreach to our friends and contacts. Our daughters’ futures depend on it, and we all must get involved if we are to turn the possibility of a cure into a reality.

My respect for Monica and for RSRT as an organization, already great when I started, has only grown.  I wanted to work for RSRT because I knew it did one thing and one thing only—supported research to find a cure.  This is what I want.  This is what we all want.  I’ve worked in the non-profit world long enough to know that a 4% administrative cost rate is remarkable.  The fact that RSRT spends 96 cents of every dollar directly on research is a reflection of its dedication, efficiency, and integrity.  This is not an organization that is flashy or that spends a lot of time or money promoting its accomplishments; instead it focuses on finding a cure for Rett Syndrome.  The result is, well, results.  It is RSRT-supported scientists who are accumulating the knowledge needed to take the next steps in gene therapy and other promising approaches.  I can talk about RSRT this way because I’m still new and in a way I’m looking from the outside in, as a parent.  I have had nothing to do with this organizational culture myself; it is driven by Monica, by the RSRT trustees, and by the families that support us.

I have learned a lot about the science behind Rett Syndrome.  I have much more to learn, but I know enough to say definitively that a cure is much more than a dream.  It is a very realistic possibility.  But it’s not going to happen unless we grow RSRT’s financial resources above and beyond the funds we raise from existing events.  Money matters in scientific research.  The more money RSRT has, the more resources it can put into projects like the Gene Therapy Consortium, and the faster and more efficiently these projects are likely to lead to a cure.

I know this has turned into a pitch—not for your dollars, but for your involvement. I am somewhat of a shy person by nature, so I guess I’ve also learned over the last year not to be shy about asking for help. There is so much to gain by it. We need more of you—as many Rett families as we can get—involved and supporting RSRT. Whether you are a parent, grandparent, aunt or uncle, cousin, or sibling—start an event of your own; support an existing event and get friends to join you; do a letter writing campaign. I know all of our lives are busy and full of the challenges of Rett Syndrome. If you can’t do a lot, do a little. But do something. It all makes a difference.

To all of you reading this who are involved already, this is a big thank you.  None of what RSRT does would be possible without you.

I have one further thought.  I know it’s hard to consider ourselves fortunate. My wife and I often find ourselves asking why us—why did our beautiful, bright-eyed daughter get such a bad roll of the dice? But when I take a step back and look at the bigger picture, I see that we are very fortunate.  We’re fortunate that scientists have pinpointed the cause of Rett Syndrome; we’re fortunate that Adrian Bird demonstrated that Rett is a reversible condition; we’re fortunate that the best geneticists and neurobiologists in the world are now attracted to Rett research and are taking the next steps on Prof. Bird’s discovery; we’re fortunate that we have RSRT to lead, support, and push forward the science; and we’re fortunate that we have a cause that speaks to people so compellingly and with so much promise. Most of all, we are fortunate to have our daughters; to love them and to be loved by them in such a profound and special way; and to see brightness in their futures.

I look forward to hearing from you. Thank you.

Tim Freeman

 

We need your help!  With promising new research projects underway such as the Gene Therapy Consortium, now more than ever RSRT needs families affected by Rett Syndrome to get involved and raise funds.  Here’s what you can do:

  • Start a new event.  Anyone can start an event—parents, grandparents, brothers and sisters, aunts and uncles.  Events can be whatever you want them to be—a gathering in a home, a picnic in a park, or a big gala.  We can help you with ideas and planning.
  • If you live in an area that already has an RSRT event, please get involved.  Come to the events and get friends to join you, ask for sponsorships, and donate auction items.
  • Do a letter-writing campaign to your friends and contacts.  This is easy to do, and we can help.  Most people are thrilled to support our cause.  But they need to learn about it and be asked.  A thoughtful letter from you can do this.  We can help you draft it and even mail it out for you.
  • Raise funds online.  This is easy and fun to do.  Go to FirstGiving and click on “Start Fundraising.”  You can do this for an occasion like a birthday or anniversary, for a run or a walk, or in honor or memory of someone.

We need all hands on deck.  Rett research is poised for breakthroughs, but we need help from the entire Rett community.  To get started, contact Tim at 609.309.5676 or tim@rsrt.org.  Thank you!

by Monica Coenraads

There is no mystery about why a girl suffers from Rett Syndrome. The cause is the mutated copy of the MECP2 gene inhabiting her cells.  But since MECP2 is on the X chromosome and all females have two X’s, beside each mutated gene rests a healthy but silenced twin. What if we could replace the flawed gene by reawakening its silenced counterpart? If we could wake up MECP2 in enough cells we could conceivably reverse Rett symptoms.

healthy-mutant

This is an approach that RSRT has championed since our launch in 2008. We are funding seven labs that are pursuing this line of work.

You may ask why do we need multiple labs working on the same goal. Isn’t that a waste of effort and money? The answer is a resounding “NO”. While the end game is the same each lab is using a different strategy to get there.

For example, the types of cells that labs are utilizing are different. Ben Philpot and colleagues at UNC are working with mouse neurons, Toni Bedalov and Jeannie Lee are using fibroblast cells, others still are using human cells. Each cell type has its own set of advantages and disadvantages.

The labs are also using different “reporters” – meaning how the cells are designed to detect activation of MECP2. Different compound libraries at different concentrations are being screened. Compounds are also being screened at various degrees of high and low throughput. And finally different criteria are being employed to define a “hit” (drugs that reactivate MECP2).

Bryan Roth

Bryan Roth gives us a tour of his robotic high-throughput
screening facility at UNC Chapel Hill

Having multiple labs attack this problem gives us more shots on goal and added assurances regarding the quality of any potential hits.

Two weeks ago we gathered everyone tackling this approach and brought them together for two intense days of talks and discussions.

Targeting MECP2 as a Treatment Strategy for Rett Syndrome
Chapel Hill, NC
May 12-13, 2014

Seventeen scientists from eight labs plus advisors from NIH and industry at RSRT meeting.

Seventeen scientists from eight labs
plus advisors from NIH and industry participate at meeting in Chapel Hill, NC.

 

Over the past 15 years I’ve organized dozens of meetings and before each one I worry – will the discussions be forced or will they flow naturally? will collaborations ensue? It was no different with this meeting.  The first few talks of the day however quickly put me at ease.  While a number of common hits were reported in multiple labs much validating and further screening remains to be done.  At the meeting, and in emails and phone calls since, the scientists are working out the logistics of validating each others hits, trading cell lines and compounds.  Exactly the outcome I was hoping for.

Last year RSRT awarded a $750,000 grant to Michael Green,  PhD of University of Massachusetts to pursue an unconventional approach to reversing Rett: reactivating the silent X chromosome.  UMASS just released the piece and video below highlighting Dr. Green’s work.  We are struck by the following quote from Dr. Green:  “With NIH funding, you pretty much have to be doing mainstream research. The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

We thank all of our supporters who make it possible for us to fund innovative, out-of-the-box projects that we believe will move us towards a cure for Rett by leaps rather than small incremental steps.

From the UMASS Med NOW website:

UMMS scientist aiding a mother’s quest for rare disease cure
With a $750,000 grant from the Rett Syndrome Research Trust, Michael Green is working to reverse a debilitating neurological disease

By Lisa M. Larson and Bryan Goodchild (UMass Medical School Communications)

Monica Coenraads is discussing work with two business associates in the living room of her Trumbull, Conn., home on a recent spring morning, when the conversation turns to the benefits of face-to-face communication over reliance on electronic devices.

Suddenly, a squeal of laughter erupts from the other side of the room, where her 17-year-old daughter, Chelsea, has been relaxing on the couch, quietly listening to her mother’s every word.

“Chelsea thinks it’s funny, because she believes her mom spends too much time on her phone,” explains Coenraads, who works from her house.

In homes across America, parents and kids are debating texting, cell phones and screen time.

But for the Coenraads family—Monica, husband Pieter, and sons Alex, 15, and Tyler, 14,—the focus is on discovering any method by which Chelsea can communicate. The slender, brilliant-blue-eyed girl, who bears a striking resemblance to her mother, has Rett syndrome, a rare, genetic, neurological disease that locks her thoughts inside her head, as she is unable to speak or to use her hands. With great determination and without speech or hand gestures, Chelsea expresses herself by focusing her gaze on pictures in a three-ring binder of the words she’d like to say.

“A child with classic Rett syndrome is in a wheelchair, unable to talk, fed through a feeding tube, with seizures, anxiety, orthopedic issues, scoliosis, contractures and no hand function,” said Coenraads, co-founder and executive director of Rett Syndrome Research Trust (RSRT) and its director of research. The former restaurateur is credited with helping to raise more than $37 million for research into Rett syndrome since her daughter’s diagnosis 15 years ago.

“They’re really trapped,” continued Coenraads, explaining the disease, which affects approximately 16,000 girls across the country. “They can understand what is going on; cognitively they are quite on track.”

UMass Medical School scientist Michael R. Green, MD, PhD, globally known for his work in gene regulation, keeps the image of Chelsea and that of other girls who suffer from Rett in mind as he works toward finding a drug that would reverse the disease. Dr. Green, a Howard Hughes Medical Institute Investigator, the Lambi and Sarah Adams Chair in Genetic Research and professor of molecular medicine and biochemistry & molecular pharmacology, received a $750,000 grant from RSRT for research aimed at reversing the underlying cause of the disorder. He is one of several dozen researchers around the world, recruited by Coenraads, who have met children with Rett and their parents, and are working on therapies, a cure or a reversal of the disease.

Rett syndrome is caused by a mutation of the gene on the X chromosome called MECP2 that causes numerous devastating symptoms that worsen over time. The symptoms begin in early childhood and leave Rett sufferers completely dependent on 24-hour-a-day care for the rest of their lives. While the function of MECP2 remains elusive, scientists know that it acts globally and impacts numerous systems in the body.

Female cells have two X chromosomes and therefore two copies of the MECP2 gene, and mutations occur in only one of the two copies of the gene. In females, however, one of the two X chromosomes is randomly turned off (or silenced), a phenomenon called X chromosome inactivation (XCI). As a result, in patients with Rett syndrome, half of the cells express a normal copy of MECP2 and the other half express the mutant copy. Importantly, in those cells that express the mutant MECP2, the normal copy is still present—just silent. Green is testing drugs that modulate XCI to reactivate the silent normal MECP2 gene in these cells as a strategy to reverse the disease.

“He is taking a somewhat unconventional approach, as he is attempting to reactivate the entire X chromosome and not just MECP2,” saidCoenraads. “His work first came to RSRT’s attention in 2009. We learned that he was conducting a screen to identify genes that control XCI. As his work matured over the next few years he did indeed identify factors that control XCI, some of which belong to molecular pathways for which there are drugs. These drugs can now be tested in culture and in vivo in Rett syndrome mouse models.”

Green praised the support he has received from RSRT and said the work that Coenraads and her colleagues do is inspirational.

“With NIH funding, you pretty much have to be doing mainstream research,” said Green, who was recently elected to the National Academy of Sciences. “The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

Read in its entirety

If you’ve ever wondered why a Rett diagnosis is based on clinical features and not a positive MECP2 test or if you have a child with a Rett diagnosis but no MECP2 mutation or the other way around then this is a video for you. What exactly does atypical Rett mean and should individuals with CDKL5 and FOXG1 mutations be considered Rett? All these topics are covered in the video below.

[video transcript]

by Monica Coenraads

Variations in our genome are what make us unique. It’s also what predisposes or protects us from disease.  For example, you may know people who eat high fat diets and yet have low cholesterol or people who, although they have never smoked, succumb to lung cancer, like Christopher Reeve’s wife, Dana.

I’ve had the opportunity to meet girls with MECP2 mutations and normal X chromosome inactivation that are too high functioning to be diagnosed clinically with Rett Syndrome. These are girls who may walk, run, speak, write, draw, and in some rare instances even speak multiple languages and play an instrument. So what is protecting these individuals from having full-blown Rett?  You guessed it: modifier genes.

Those of you familiar with RSRT’s efforts know that we have been funding a project in the lab of Monica Justice aimed at identifying protective modifiers in mice.  This past summer the Justice lab published the first modifier that suggests that statins (drugs that lower cholesterol) may be treatment options for Rett.   More modifiers are likely to follow.

In the last few years a number of factors have coalesced to make the hunt for modifiers possible in people: 1) the identification of a growing number of individuals with MECP2 mutations who are too high functioning to fit the criteria for a clinical diagnosis of Rett  2) dropping costs for exome sequencing  3) improved bioinformatics which allow for better analysis and interpretation of the vast quantify of data generated from sequencing.

In light of these developments RSRT has awarded $314,000 to Jeffrey Neul at Baylor College of Medicine to sequence the exomes (the protein producing portion of the genome) of high-functioning kids/adults in the hopes that some common variables may point to modifiers which can then become drug targets.

Importantly, the sequencing and phenotypic data will be a valuable resource as it will be deposited into the National Database for Autism Research and available to the scientific community.

We need the Rett community’s help to identify high-functioning individuals who Dr. Neul may not be aware of.
If you think your child may qualify please contact me at monica@rsrt.org

Watch the interview below with Dr. Neul to learn more about this project.

[video transcript]
[video transcript – Chinese]

by Monica Coenraads

[Italian translation]
[Spanish translation]
[Press Release]

Faced with the complex problem of discovering the elusive function of the Rett protein, RSRT set out to conduct an experiment of our own. We shook the conventional practice of laboratories working in isolation and instead convened three scientists to work collaboratively: the MECP2 Consortium. We gave them the necessary financial resources and provided infrastructure including in-person meetings. The results surprised us all.

Adrian Bird

Adrian Bird

Michael Greenberg

Michael Greenberg

Gail Mandel

Gail Mandel

The MECP2 Consortium was launched in 2011 with a $1 million lead gift by Tony and Kathy Schoener.
RSRT has committed an additional $3.4 million of funding to the Consortium.
We are extremely grateful to the Schoeners for their second $1 million pledge to support this effort.

The Consortium quickly reported significant advancements. The Mandel and Bird labs showed, for the first time, a dramatic reversal of symptoms in fully symptomatic Rett mice using gene therapy techniques that could be utilized in people.

The “Rett mouse” moving around received healthy Mecp2 via gene therapy. The immobile mouse did not receive treatment. The video was taken four weeks after treatment.

The Bird lab discovered that the function of the Rett protein, MeCP2, depends on its ability to recruit a novel binding partner, NCoR/SMRT to DNA. Disrupt that ability and the symptoms of Rett ensue.

The Greenberg lab built on the work of the Bird lab and discovered that adding a phosphate group to MeCP2 alters its ability to interact with NCoR/SMRT and affects the expression of downstream genes.

While the clinical implications of the gene therapy experiments are obvious some may think “so what?” when it comes to the NCoR experiments.

I suspect that in the mind of many Rett parents the best evidence of research progress is clinical trials. However, this is often not the best measure of progress.

Thomas Südhof, recent Nobel Laureate, recently commented  “I strongly feel that attempts to bypass a basic understanding of disease and just to get to therapies immediately are a misguided and extremely expensive mistake. The fact is that for many of the diseases we are working on, we just don’t have an understanding at all of the pathogenesis. There really is not much to translate. So NIH and many disease foundations are pouring money into clinical trials based on the most feeble hypotheses.”

So I will argue that investing in a better understanding of MECP2 – a primary goal of this Consortium – is money well spent, as it will add to our current arsenal of strategic approaches to combat Rett.

A repurposed drug may partially treat some of the symptoms, but to achieve the kind of dramatic improvement that most parents and I ache for will likely require attacking the problem at its very root.

As Rett parents will attest to the symptoms of the disorder are numerous and devastating. Whatever MECP2 is doing, it’s acting globally on many systems in the body. A repurposed drug may partially treat some of the symptoms but to achieve the kind of dramatic improvement that most parents and I ache for will likely require attacking the problem at its very root.

There are multiple ways to achieve this end goal: gene and/or protein therapy, activating the silent MECP2, modifier genes. These are all areas in which RSRT is financially and intellectually engaged with.

In parallel, however, it is imperative to understand what MECP2 does. RSRT has therefore committed an additional $3.4 million of funding to the MECP2 Consortium. We are extremely grateful to Tony and Kathy Schoener for their second $1 million pledge to support this important project.

I recently discussed the experiences of the past few years and what lies ahead with the Consortium members.

Greenberg: Research in neuroscience is undergoing a revolution. We now have the technologies in hand to solve some of the most difficult neurobiological questions. However, progress towards answering these hard questions requires scientists working together. A single lab working alone doesn’t have the expertise or the resources to make significant progress when the scientific problem is particularly challenging.

The MECP2 Consortium is a model for something much bigger: how neuroscience overall needs to operate so that we can find therapies and cures for disease.

The MECP2 Consortium is a model for something much bigger: how neuroscience overall needs to operate so that we can find therapies and cures for disease.   We are scientists in different parts of the world, working together, sharing their results long before publication, and brainstorming openly on a regular basis.  The different perspectives of the three labs allow for a wonderful exchange of ideas to advance the science. I believe this is what the Consortium is all about.  We have ignored the typical barriers of geography and have brought together scientists from Edinburgh, Portland, and Boston on a regular basis.  The results have been stunning.  There has been much more rapid progress than would have been made by the individual labs.

Consortium meeting in Boston in November of 2013.

Consortium meeting in Boston in November of 2013.

Bird: I agree. An over arching goal of the Consortium is to understand the way the MECP2 protein works at the molecular level.  We are at last starting to make real progress on this and will be testing some of the new ideas in cellular and animal models.  Our ultimate aim is to use this new knowledge to provide rational approaches to therapy.

Mandel:  Front and center is always our goal to find a therapy for Rett. This guides our experiments and keeps us focused. The fact that financial support comes from families who have a child with Rett and their networks makes us work harder.

Coenraads: In your opinion what are the elements that have made this consortium “work”?

Greenberg:  Trust and openness, a willingness on the part of all three Principal Investigators to talk through any potential problems immediately as they come up.  A willingness to check egos at the door so that we can work together for something that is more important than our individual advancement. Importantly the participants, Mandel, Bird, Greenberg and Coenraads like and trust each other.

consortium4Bird: We all have different backgrounds and interests, but we share a commitment to understanding Rett Syndrome.  We compliment each other surprisingly well.

Mandel:  The regular meetings and exchanges and the quality of the scientists involved have been key factors as well as the availability of sufficient funding for each of us to follow our scientific noses.

Coenraads:  Fortunately science is not linear. There are technologies available now that weren’t available when the Consortium started. How does this impact your Rett research?

Greenberg:  There are a lot of new technologies available – in particular Cre lines that will allow us to study the effect of MeCP2 loss in a relatively homogeneous population of neurons, CRISPR and Talen technology that will facilitate gene correction, and genomic technologies that are providing a new understanding of the role of methylation in the control of neuronal gene expression.  Also, better equipment, such as microscopy will help.

Bird:  The technologies for genetic modification have existed for a decade, but the advent of CRISPR has made this facile.  Being able to edit genetic mistakes in patients is no longer a science fiction dream, but has become a real possibility.  Exploring this option will be an important focus for the Consortium.

Coenraads:  Harrison Gabel from Mike’s lab recently shared with me in an email:  Our group meetings are essential to critically assessing our work. Each lab group has its own “world view,” and having that view shaken up every six months is very constructive.

So I look forward to lots more critical assessments and worldviews getting shaken as together we get to the bottom of what MeCP2 does.


* Due to the success of the MECP2 Consortium, and its positive gene therapy findings, RSRT has just announced funding for a second consortium: the MECP2 Gene Therapy Consortium. Read more about this newly formed second collaboration.

by Monica Coenraads

[Italian translation]
[Spanish translation]
[Press release]

The videos below are perhaps the most well-known in the Rett community. If you love a child with Rett then chances are you’ve watched them obsessively.

This work published in 2007 by Adrian Bird, declared to the world that Rett is reversible, but did not tell us how this could be done in people.

Fast-forward six years and the video below from the RSRT-funded labs of Gail Mandel and Adrian Bird may have given us an answer: gene therapy.

The mouse moving around was given gene therapy treatment and received healthy Mecp2 gene. The immobile mouse did not receive treatment. The video was taken four weeks after treatment.

So how do we make the giant leap from recovered mice to recovered children?

To move us towards this goal, RSRT has launched their second collaborative group – the MECP2 Gene Therapy Consortium. This new group comes after the success of RSRT’s MECP2 Consortium, established in 2011, that led to the initial encouraging gene therapy findings. With a budget of $1.5 million the members of this international gene therapy collaboration are charged with tackling the necessary experiments to get us to clinical trials as quickly as possible.

I recently caught up with the investigators to discuss this novel collaboration:

Brian Kaspar (Nationwide Children’s Hospital)
Currently working on gene therapy clinical trial for Spinal Muscular Atrophy

Stuart Cobb (University of Glasgow)
Neurophysiology lab and co-author on 2007 reversal paper with Adrian Bird

Steven Gray (UNC Chapel Hill)
Currently working on gene therapy clinical trial for Giant Axonal Neuropathy

Gail Mandel (OHSU)
Member of MECP2 Consortium and author of gene therapy paper published this summer

Brain KasparNationwide Children's Hospital

Brain Kaspar

Stuart CobbUniversity of Glasgow

Stuart Cobb

Steven GrayUNC Chapel Hill

Steven Gray

Gail MandelOHSU

Gail Mandel



Coenraads:  Let’s jump right in. Why Rett? Why now? 

Cobb: While there have been major advances in understanding the molecular actions of the MeCP2 protein, it is still difficult to conceive of a small ‘traditional’ drug molecule being able to mimic its function. While traditional drug approaches will likely be restricted to correcting specific aspects of what goes wrong in Rett it is conceivable that gene therapy can correct the cause of Rett at its very source and thus provide a profound recovery of function.

While traditional drug approaches will likely be restricted to correcting specific aspects of what goes wrong in Rett it is conceivable that gene therapy can correct the cause of Rett at its very source and thus provide a profound recovery of function. – Stuart Cobb

Mandel:  It has been known for some time now that when MeCP2 is expressed genetically in cells throughout an MeCP2-deficient mouse, major Rett symptoms are reversible in mice.  Two of the big outstanding questions then are: 1) Will this be true for humans and 2) Can we add MeCP2 back to patients and also achieve reversal?  The first question is currently still an open question, although upcoming experiments using human neurons and astrocytes derived from iPSCs and xenografts (transplanting human cells into mice) may provide some important clues. The second question is challenging because currently there are no reliable ways to introduce MeCP2 throughout the brain, although recent studies in mice, funded through RSRT consortiums, suggest that AAV9-mediated transduction (delivery via a virus) might have potential. Therefore, two advancing technologies, iPSCs and AAV9 viruses, are converging to compel us to jump right in now.

Kaspar: A major advantage in Rett is that the genetic target is defined for us: MeCP2.  Another advantage is that it’s not neurodegenerative – neurons don’t die.  And importantly, we know that restoring the proper level of MeCP2, even later in life, at least in a mouse, results in dramatic improvements.

Why now? Because the gene therapy field now has an arsenal of powerful new tools.  We have at our disposal a tool kit that can express genes for long periods of time and that can target many cell types efficiently throughout the entire nervous system. Our challenge will be to utilize our toolkit to hit the precise cells at the right expression levels.  I’m certain we can accomplish this goal.

Gray: That said, the devil is in the details.  We have to get MeCP2 broadly distributed throughout the whole brain, which is something that has been done in animals but not yet in humans.  Just as important, we have to be very careful to get the level of MeCP2 correct – too little may not work well enough and too much could cause a different spectrum of disease.

Coenraads: What have we learned thus far regarding gene therapy for Rett?

We’ve learned that a single one-time administration of a gene therapeutic can have a clinically meaningful result in the workhorse rodent model of this disease, even when delivered later in life. The results have been quite promising, and now multiple laboratories have similar promising results, it’s not just an isolated manuscript happening in one laboratory. – Brian Kaspar

Kaspar: We’ve learned that a single one-time administration of a gene therapeutic can have a clinically meaningful result in the workhorse rodent model of this disease, even when delivered later in life.  The results have been quite promising, and now multiple laboratories have similar promising results, it’s not just an isolated manuscript happening in one laboratory.  Using similar approaches, multiple groups have encouraging results.  That’s good for science and that’s good for Rett patients.

Steve Gray (far right) and Stuart Cobb (second from the right) at an RSRT science meeting in late 2012.

Steve Gray (far right) and Stuart Cobb (second from the right) at an RSRT science meeting in late 2012.

Cobb:  The studies have also shown that the level of MeCP2 protein produced by the gene therapy is not producing any obvious defects in its own right and it therefore seems possible to deliver protein within limits that are tolerable to cells.

We have also learned that it is not necessary to ‘hit’ all cells with the virus, this is never going to be achievable in practice anyway. Fortunately, a substantial therapeutic impact may be achieved by delivering the gene to a subset of cells. Of course the absolute number of cells, the types of cells and location in the brain is likely to be very significant. These are important issues that will be investigated by the MECP2 Gene Therapy Consortium.

Gray: Finally, the studies tell us that we have to be very careful how we target the MeCP2 gene, to make sure too much isn’t delivered to a particular organ, such as the liver.

Coenraads: Have you ever worked in collaboration with multiple labs?  What do you think are the advantages?  Could there be disadvantages?

Mandel: I have been fortunate enough to be part of a productive collaboration funded by RSRT to work on how MeCP2 functions normally, and in mutants, and to do, with Kaspar’s group and Adrian Bird, the initial pilot proof of principle for gene therapy for Rett, using AAV9 vectors.

Gray:  Most of my work is done in collaboration with other labs, and I’m very comfortable doing research that way.  I have a small and fairly specialized lab.  We aren’t experts at everything, and it is much more efficient to collaborate with someone that has expertise than try to develop it on your own.  This speeds things up and raises the quality of the work.  The keys to making it work are that everyone has to be fully committed, and there has to be a level of trust across the members of the consortium.  Trust that you can share data openly, and trust that the work is being carried out to the highest standards.  If one investigator isn’t doing their part or does sloppy science then things can fall apart.

Stuart Cobb (right) with David Katz.

Stuart Cobb (right) with David Katz.

Cobb:  I have enjoyed a number of successful bilateral collaborations in the past but the formation of the four-lab Consortium is going to be a new venture for me. Clearly there will be big advantages in terms of pooling complementary expertise to make swift progress. However, there will also be challenges, one being the necessity to maintain very good communication within the Consortium to coordinate our efforts and work together efficiently.

Kaspar:  My laboratory is engaged in a number of collaborations and they are a major reason we have been successful.  Our international collaborations have given us access to patient samples as well as opened the door to new ideas and interactions that just couldn’t be accomplished sitting in isolation. Collaborations bring everyone’s experience and expertise to the table and allow the participants to rapidly answer difficult questions. We don’t always have to reach consensus but the right team will be open to sharing ideas and comfortable with hearing criticism as well as be aligned on goals and focused on the patients.

Coenraads: What are the strengths your lab brings to the table?

Steve Gray in his lab at UNC Chapel Hill

Steve Gray in his lab at UNC Chapel Hill

Gray:  We are part of one of the best gene therapy centers in the world, with a vector core facility that makes hundreds of research preps and several clinical preps each year.  My lab in particular has, as its primary goal, a mission to develop nervous system gene therapy platforms.  We’ve made enormous strides using existing vectors to their full potential, and also leading the way to develop newer and better vectors.  Also, our experience bringing our Giant Axonal Neuropathy project to clinical trial gave us experience on the process of moving a biological from the bench to the bedside. 

Cobb:  My own lab brings expertise in the neurobiology side in terms of accurately mapping out Rett syndrome-like features in mice and within the brain and being able to assess in detail the ability for gene therapy to improve aspects of the disorder.

Mandel:  I am a basic science lab and I have strengths in applying state of the art molecular tools to questions related to gene therapy.  My lab also has much expertise in histology of the brain.

Kaspar: We have successfully navigated two programs from bench research to human clinical trials.  We have flexibility to focus on complex basic biology questions, while keeping in mind our goal to advance therapies towards human clinical trials.

Coenraads:  Gene therapy has had a rocky road. How do you view the field at the moment?

Kaspar:  Expectations and promises were far too high in the early days of gene therapy. I think transformative therapies go through this track of failing and then triumphing. One simply has to look at the field of organ transplantation as an example. I think gene therapy will triumph, but we still have much to learn and pay attention to. There is a great deal of excitement and hope in the field today.  We have to be good custodians of this technology with laser focus on safety and design of human clinical trials.

Gray:  There are a lot of good things happening in the field right now with patients seeing major improvements in their lives as a result of gene therapy.  The first gene therapy product received full regulatory approval last year in Europe.  Biotechnology companies are taking an interest in gene therapy.  Frankly, it is a good time to be in the field.

Modern, safer, approaches to gene therapy are developing very rapidly and it is one of the most vibrant fields in the genetics and molecular medicine arena at the moment. – Stuart Cobb

Mandel: I think that there is a large and growing momentum now for gene therapy because of the huge advances in molecular biology and viral technologies.

Coenraads: I find that the gene therapy area is polarizing – people love it or hate it – have you encountered a similar response?

Cobb:  Yes, I have indeed encountered such contrasting views. Even within the community of Rett clinicians, I have had views of gene therapy being ‘the obvious route to follow’ versus others expressing great skepticism. Interestingly, the view within industry has been more accepting, perhaps due to the massive shift towards biologicals (alternatives to classical small molecule drugs) that has occurred in recent years.

Kaspar:  Typically those that are not fans of this technology focus on past failures. With any transformative findings there will be disbelievers.   I’m reminded by a quote from Alexander von Humboldt:  There are three stages of scientific discovery: first people deny it is true; then they deny it is important; finally they credit the wrong person.

Gray:  I can’t blame some people for hating it.  Gene therapy promised a lot early on, before the technology was very developed.  Expectations should have been tempered somewhat while the science was worked out, but instead the field moved too fast and people got hurt.  That said, I don’t think you should turn your back on a potentially revolutionary medical technology because of mistakes made over a decade ago when the field was in its infancy.  If you take a fresh look at the things happening today, there is a lot of real and well-founded optimism.

Gail Mandel at a recent RSRT meeting.

Gail Mandel at a
recent RSRT meeting.

Mandel:  As in any area of science, there are proponents and detractors.  There are technical issues with gene therapy, such as scaling and side effects that need to be addressed before more people will lose some skepticism, although some skepticism is quite healthy and pushes us to be as rigorous as possible.



Coenraads: Dr. Kaspar, tell us a bit about your experience bringing the Spinal Muscular Atrophy project to clinical trial.   How long did it take from mouse experiments to trial? How much money was invested from your lab?

Brian Kaspar (middle) at an RSRT workshop.

Brian Kaspar (middle) at an RSRT workshop.

Kaspar:  Our SMA program is quite exciting. We discovered the unique capacity for AAV9 to cross the blood brain barrier in 2009, in 2010 we were in progress to have the longest living SMA mouse in the world. We further tested safety and navigated the regulatory process including the NIH Recombinant Advisory Committee, the Food and Drug Administration and our institutional review board.  Late in 2013 we were granted approval from the FDA and we will be injecting our first patients in a Phase 1/2 clinical trial early this year.  It was a hectic 3-year process that cost $4 million and counting.  We are excited and hopeful to help children with SMA type 1.

Coenraads:  Dr. Gray, you are developing a gene therapy treatment for a disease called Giant Axonal Neuropathy.  Can you tell us about your experience with that project? How far from clinical trials are you?   How long did it take from mouse experiments to trial? How much money did it cost?

Gray:  My GAN project has been life changing.  This was the project that made the connection for me to patients and changed the way I think about research.  Before then it was just about getting a good paper, or a grant, or doing the right things to advance my career.  Now it is about making a real difference in the lives of people I’ve come to know and love.  We’re on track to treat the first patient in the first half of 2014. We developed the treatment about 3 ½ years after starting the project, which included testing the treatment in the laboratory and developing an approach that should translate to humans.  It’s taken another two years to start the trial. Our preclinical supporting studies were approximately $1.5 million.  The FDA-required safety studies were another $0.75 million.  We are budgeting another $1.5 million for the clinical trial. Most of these funds were provided by a small grass-roots foundation called Hannah’s Hope Fund.

Coenraads:  I’m delighted that you have all agreed to collaborate. I look forward to our bi-monthly phone calls and in-person meetings twice a year.  Parents all over the world will be waiting anxiously to hear about your progress. As you know, there is a lot at stake.

by Katie Bowers and Monica Coenraads

Sometimes, new ideas come from the strangest of places; inspired by something that seems completely unrelated. This sort of out-of-the-blue brain blast is exactly what happened in 2012 when a study about bacteria’s adaptive immunity opened up the possibility for a new approach to gene therapy. While CRISPR technology was runner-up for the Breakthrough Technology of the Year in 2012, its presence in bacteria cells has been known since 1987. It was not until a series of studies between 2005 and 2007, however, that their role in the bacterial adaptive immunity was revealed.

Short for Clustered Regularly Interspaced Short Palindromic Repeats; a CRISPR is a small length of DNA with a repeating and reversing sequence of base pairs (the pieces that make up genetic code). Found in a specific section (or loci) in the bacterial genome, multiple CRISPRs are usually grouped together in a string. Each CRISPR is followed by a ‘spacer’ section of DNA.

When pathogens, such as a virus, attack bacteria they insert a section of DNA into their victim. Oblivious to any danger the victim reads and processes this foreign DNA. In so doing, the bacteria also retain a record within its spacers enabling it to recognize and fight off the same pathogen in the future. Each spacer therefore acts as a ‘bookmark’ for any pathogen attack the cell has encountered.

How do bacteria do this? Preceding a CRISPR sequence are cas genes which make enzymes that copy the foreign DNA sequence and insert it as small fragments into the bacterial genome as new spacers.

With this new spacer now available in the CRISPR loci, the next time a bacteria encounters the same attack it will recognize the foreign DNA and send out a secondary Cas protein to target, bind, and splice out the DNA thereby inactivating the invader, analogous to the way in which our bodies produce antibodies against repeated infections

It’s this ability to identify, isolate, and splice out a specific piece of DNA that has captured the imagination of scientists.

The CRISPR/Cas system can now be hijacked to accurately target genetic errors in DNA and remove them. Once removed repair systems kick in to fix the sequence. This can be done either of two ways: non-homologous end-joining which simply connects the two ends together or the more sophisticated homology-directed repair.

Image: Courtesy of Broad Institute

Image: Courtesy of Broad Institute

Applying this to Rett Syndrome we can use the following example. The most common mutation in MECP2 is the T158M where a cytosine to thymine error at nucleotide base number 473 swaps a methionine amino acid for a threonine. One could envision using the CRISPR/Cas technology to introduce a cut at nucleotide base number 473, splice out the thymine and provide a cytosine base via a template. Cas enzymes and base repair templates would be delivered via gene therapy vectors.

So where does the technology currently stand to be able to achieve this? Inducing the break in DNA can now be achieved efficiently and effectively however the repair step using templates is not yet ready for prime time as efficiency rates (the number of cells that actually achieve repair) are still quite small. Before the technology can be considered for therapeutic applications it also needs to be shown that the CRISPR/Cas machinery only cuts the DNA at desired sites as additional “off target” breaks could be damaging.

The encouraging news is that progress with CRISPR/Cas technology is occurring at lightning speed with thousands of laboratories around the world working to improve the process. It is not difficult to imagine the immense possibilities for treating genetic disease. No wonder there is so much excitement with scientists themselves routinely referring to this new technology as revolutionary.

Press Release Announces Tim’s Hire

Dear Friends,

Tim-and-Eleanor-2A year and a half ago my wife, Rachel, and I received the worst phone call of our lives—it was the Children’s Hospital of Pennsylvania informing us that our beautiful, bright-eyed, giggling two-and-a-half year old daughter, Eleanor, had tested positive for the MECP2 mutation that causes Rett Syndrome.  We were simply devastated and didn’t know what to do or where to turn.  The ensuing months were the hardest of our lives.  Our dreams and hopes for our only child had been crushed.  We watched helplessly as Eleanor stopped scooting on her rear end, as she had been doing, and developed a repetitive hand motion and other symptoms.

Several months later, Rachel found the RSRT website.  We made a call and RSRT’s co-founder and executive director, Monica Coenraads, answered the phone.  We soon learned that we were not alone in our sadness and that there was a community of wonderful, supportive parents, grandparents, family members, and friends of families who have been impacted by Rett Syndrome.  And even more exciting, we learned that there was hope for a cure for Rett.  In fact, it was clear that there was a good deal more than hope—Rett symptoms had been reversed in an animal model, and very promising scientific progress was being made, much of it encouraged and supported by RSRT.

Monica and I continued to correspond.  I was seeking her advice and thoughts about Eleanor’s diagnosis, and I was trying to understand the research and science.  Monica began seeking my advice about fundraising and public relations when she learned that I headed the development office of the Woodrow Wilson Foundation in Princeton, New Jersey, and before that had served as director of development at Columbia University’s Teachers College.  It may have dawned on Monica and me at the same time that there was a fit here—that I cared deeply and personally about the work that RSRT was doing and that I had nearly 20 years of experience that could help grow RSRT and its impact on the lives of girls and women with Rett.

Tim-and-EleanorThe rest, to use the cliché, is history.  My first official day as a Program Director at RSRT was June 17.  Under Monica’s direction, I’m responsible for fundraising, public relations, and strategic thinking about the organization.  I couldn’t be more excited.  So many people, Monica foremost among them, have worked so hard and contributed so much to making RSRT the respected force that it is and to building the cumulative scientific knowledge that will lead to a cure.  I’m honored and humbled to join this team.  Frankly, I never imagined that I would be able to put my knowledge and skills to use for something so important to me.

I’ve gone on longer than I intended, but I have one further thought.  I’ve been thinking lately about President Kennedy’s 1961 speech to Congress in which he announce the dramatic and ambitious goal of sending an American to the Moon before the end of the decade.  It took a huge team effort, conviction and confidence in a very clear mission, ample resources, and leadership, for the goal to be met.  I think RSRT’s goal is not unlike President Kennedy’s in its ambition, its clarity, its importance, and its attainability.  I also believe that all of us working together are the team that will get us to the moon.  And, like building a rocket, a cure depends on cumulative knowledge that is the sum of its parts.  The rocket needs its nose cone, its fuel tank, its electronics, its landing pads, and other components to meet the goal.  Research is like this too.  All the parts have to work together.  It is cumulative knowledge that will get us there.

Tim-and-Eleanor-3I am tremendously grateful to Monica, to the RSRT Board, and to all of you who contribute your time, energy, and resources to RSRT for your confidence in me.  I promise Eleanor and all of our daughters that I will do my best in everything I do for RSRT.  I will need your help, advice, and counsel—most of you know RSRT and all of its accomplishments and the Rett community at large far better than I do—so I hope I can call on you.  Please don’t hesitate to contact me any time.  My office line is 609-309-5676; my cell is 609-815-5102; and my email is tim@rsrt.org.  I look forward to meeting you.

Best,

Tim Freeman

RETT SYNDROME RESEARCH TRUST WEBSITE

by Monica Coenraads

This past November in a peaceful New York City suburb, twenty-eight scientists gathered for a three-day meeting organized and sponsored by RSRT.

In the age of email and Skype and webinars and GoToMeeting and a plethora of ways to connect people from across the world with a click of a mouse why does RSRT spend hard-earned money to bring scientists together for face-to-face meetings?

title-photo-tarrytown

Science Magazine Editor-in-Chief, Bruce Alberts, addresses this question beautifully in a recent editorial. “Part of the answer is that science works best when there is a deep mutual trust and understanding between the collaborators, which is hard to develop from a distance. But most important is the critical role that face-to-face scientific meetings play in stimulating a random collision of ideas and approaches. The best new science occurs when someone combines the knowledge gained by other scientists in non-obvious ways to create a new understanding of how the world works. A successful scientist needs to deeply believe, whatever the problem being tackled, that there is always a better way to approach that problem than the path currently being taken. The scientist is then constantly on the alert for new paths to take in his or her work, which is essential for making breakthroughs. Thus, as much as possible, scientific meetings should be designed to expose the attendees to ways of thinking and techniques that are different from the ones that they already know.”

I’ve organized dozens of scientific meetings since 1999. In recent years I’ve come to favor small, invitation-only meetings on clearly defined topics, hosted in quiet locations far away from distractions. I find that more intimate and focused meetings catalyze deeper discussions and are better equipped to ensure participants of confidentiality, allowing them to share data long before publication, a process that can unfortunately take many months and sometimes years.

tarrytown-collage2

The success of a meeting is measured in part by how effectively the exchange of ideas, scientific tools and ensuing projects and collaborations move the field forward. It may take considerable time for the impact of a meeting to be known. Sometimes, however, success is instantaneous, with collaborations initiated before the meeting has even concluded.  The concept for the modifier screen currently underway in the lab of Monica Justice, in which we have invested $1.5 MM, was born at a meeting I organized a number of years ago. The MECP2 Consortium evolved from interactions between Gail Mandel, Mike Greenberg and Adrian Bird at our science meetings over the last decade.

RSRT_Symposium_111312_webfinals-30

As the Rett/MECP2 field has matured, so has the nature of the science meetings. This year we heard a large number of presentations with clinical relevance; that certainly was not the case even a few short years ago. Where will the research take us in the next few years? I can’t wait to find out.

facebook  View our Facebook album to see all the pictures from the meeting and to put names to the faces.

Photo credit:  Kevin Coloton

by Monica Coenraads

                RETT SYNDROME RESEARCH TRUST WEBSITE

RSRT-award

monica-chelseaFor almost 15 years now, I’ve been immersed in the science behind Rett Syndrome. As Executive Director of RSRT I understand that the work is methodical, that good research takes time, that breakthroughs often come after many tiny, incremental steps. And yet, as a mother witnessing my 16-year-old daughter deteriorate a little more each year, I feel a great urgency to push the research harder and faster. All families with intimate, daily experiences of Rett Syndrome’s harsh rule know the longing for their children to be free and well. RSRT is one-hundred-per-cent focused on that ultimate goal – and that’s what guides our choices about where to invest not just our hard-won funds but our hopes and dreams.

2012 gave us reason to be hopeful. We are grateful for the active engagement of our trustees, the unwavering commitment of the families who fundraise for us and the generous contribution of a wide range of people who give their time and talents freely to help us achieve our goal. We wouldn’t be where we are without the unique global partnerships that we enjoy with Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation (Israel), and with national organizations such as GP2C, Kate Foundation, RMRA. Together you have produced an investment in science that will create a better future for our children.

But that future won’t just happen. Before Rett entered my life, I had never given much thought to the drug development process. Like most people, I assumed that academic scientists, industry and government worked together seamlessly to discover effective therapies for the horrible ailments that afflict us.  Nothing could be further from the truth.

There is no “Department of Cures.” Laboratory breakthroughs don’t naturally bubble up and become drugs.  The reality is that progress must be relentlessly driven, managed, nurtured and prodded, not to mention funded. It’s a messy, difficult and expensive process that can be slowed and derailed by a multitude of hurdles.

Disease-specific organizations such as RSRT cannot afford to be spectators, passively reviewing proposals and granting money. It is incumbent on us to set the research agenda and to facilitate its execution while staying nimble and vigilant to new opportunities.

Two such opportunities would not currently exist without RSRT: reactivating the silent MECP2 on the inactive X chromosome, and gene modifiers.  Following the 2007 reversal, RSRT carefully evaluated the state of Rett research and made the decision to champion these explorations before others had even realized they were, in fact, promising approaches.

Will they lead to a cure? Ongoing research and clinical trials will tell. But in the meantime, RSRT will continue to encourage and support the research that holds the greatest promise to truly change our daughter’s lives.  For we have the most to win if we succeed, and the most to lose if we fail.


READ PRESS RELEASE

2012

mecp2-activation

There is no mystery about why a girl suffers from Rett Syndrome. The cause is that mutated copy of the MECP2 gene inhabiting her every cell.  But since MECP2 is on the X chromosome and all females have two X’s, beside each mutated gene rests a healthy but silenced twin. What if we could replace the flawed gene with its perfect counterpart?

That’s the question Ben Philpot of the University of North Carolina at Chapel Hill has asked. RSRT has awarded Philpot, Bryan Roth and Terry Magnuson $2.2 million to answer it.

Philpot’s recent paper in Nature describes successful reactivation of the silenced gene in Angelman Syndrome, demonstrating that replacement is possible.

Joining Philpot and Roth in this effort is Terry Magnusson, a world-renowned leader in X-inactivation. The award will fund a team of three full-time post-docs and two technicians.

philpot-quote

The goals of the 3-year project include:

  • Screening of 24,000 compounds
  • Performing whole genome analyses to test for drug specificity to help predict potential side effects (e.g. what other genes might be affected by the drug)
  • Identifying the mechanism of MECP2 unsilencing, which will allow the prediction and design of additional therapeutic targets
  • Optimizing drug efficacy through medicinal chemistry (e.g. by designing drugs to maximize transit through the blood-brain-barrier while minimizing off-target effects)
  • Advancing lead candidates into preclinical trials.  The project will be milestone-driven, with a set of pre-established deliverables. This will allow us to monitor progress utilizing a team of advisors with relevant expertise.

Interview with Benjamin Philpot Ph.D. from RSRT on Vimeo.

justice

Along with activating the silent MECP2, RSRT has championed a second exciting approach.

In her Baylor College of Medicine laboratory, Monica Justice set out to identify modifier genes – altered genes able to dampen the ill effects of an MECP2 mutation.

The common belief has been that these genes would be hard to find.  The reality? With the screen just 15% complete, Justice has already found five. What she is seeing in mice implies that Rett-like symptoms are unstable, and consequently easier to revert to a normal state than anyone had suspected.

None of the modifier genes can suppress the disease entirely, but each reduces a subset of Rett-like symptoms.  While we had originally thought that the modifiers were specific to the central nervous system, it turns out they may operate elsewhere in the body. At least one of the modifiers suggests an alternative therapeutic target, using drugs already FDA-approved.  With RSRT funding Justice is now testing the drugs in mice and has a manuscript currently under review.  A clinical trial is being explored.

justice-katz

At RSRT we’re excited about will happen once the screen is completed. Justice is likely to find many more modifiers, some of which may point to tractable pathways. In support of this goal, RSRT has committed an additional $800K to the Justice lab, bringing its total commitment to the modifier screen to $1.5 million. This funding should provide sufficient resources to allow Dr. Justice to reach the 50 percent mark in the screen within two years – at which point she will propose a plan to us for completing the project. Many more modifiers await discovery. Further surprises are likely in store.

kipnis

We have also awarded funding of $720K to the lab of Jonathan Kipnis at the University of Virginia. Kipnis and colleagues hope to gain better understanding of the immune system’s involvement in Rett by analyzing patient blood.  The hope is that immune-based therapies can be developed.

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Previous work from the Kipnis lab suggested that bone marrow transplants could be beneficial. Before proceeding to clinical trials with a procedure that is extremely serious and risky, RSRT committed funding in 2012 for independent corroboration of these findings.

zoghbi

We are also supporting Huda Zoghbi’s work to explore whether symptoms of the MECP2 Duplication Syndrome can be reversed once the protein level is normalized. $236K was awarded to this project via the MECP2 Duplication Syndrome Fund through the fundraising efforts of the duplication/triplication families.

zoghbi-photo

drug-testing

RSRT is supporting work at John Bissonnette’s lab at OHSU (Oregon Health & Science University) to explore serotonin 1a agonists for their ability to reduce apneas, and Andrew Pieper’s lab at UTSW (University of Texas – Southwestern) for ongoing drug screening.

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Finally an award of $65K was made to Dr. Sasha Djukic for her work at the Tri-State Rett Syndrome Center in the Bronx, NY with the majority of the funds coming from the annual Reverse Rett NYC event.

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Please join me in wishing all of our scientists Godspeed. I look forward to keeping you apprised of their progress.  One last heartfelt thank you to everyone who raises research funds for RSRT. These projects are your money and your effort at work.

Photo credit: Kevin Coloton

RETT SYNDROME RESEARCH TRUST

Kelly Rae Chi

[links to podcasts are below]

That mutations in the MECP2 gene cause Rett Syndrome has been known for over a decade. But what exactly the protein does is not yet clear.

In the early 90s, Adrian Bird’s group purified MeCP2—which stands for methyl-CpG binding protein 2—and named the protein for its ability to bind parts of the DNA with a chemical tag called a methyl. Methyls tend to dampen the expression of genes, suggesting that MeCP2’s function is to silence genes.

Studies published since then suggest MeCP2 activates or represses the expression of many genes. Other results suggest that the protein binds throughout the genome, influencing the way DNA packs into a cell.

New evidence, published today (December 21) in Cell, shows that MeCP2 binds to spots throughout the genome that are tagged with the chemical, 5-hydroxymethylcytosine (5hmC) in mice, and that this interaction may be important for understanding Rett Syndrome.

“[The study is] a very interesting new development in studying the functional significance of MeCP2, which we have to understand if we’re going to understand Rett Syndrome,” says Bird, professor of genetics at the University of Edinburgh in Scotland who was not involved with work.

Abundant in the DNA of certain brain cells, 5hmC seems to be a signpost of sorts for active spots within the genome — that is, the regions that are churning out new protein — the study found. MeCP2’s latching onto these sites supports its potential role as a gene activator, though it’s clear that the case of what MeCP2 does is far from closed.

“Whether or not [MeCP2 is] directly involved in activation is still a matter of further investigation. But we know that it can localize to a region that contains 5hmC and active genes,” says Skirmantas Kriaucionis, group head in the University of Oxford Nuffield Department of Medicine, who co-led the study with Nathaniel Heintz of the Rockefeller University in New York.

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heintz-skiri

Podcast with Skirmantas Kriaucionis

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Figuring out 5hmC

As a postdoctoral researcher in Heintz’s lab, Kriaucionis found 5hmC in 2009 by accident when he was looking at how a closely related chemical, 5-methylcytosine (5mC), influences genome structure in brain cells. Anjana Rao’s group, then at Harvard Medical School, working independently from Heintz’s lab, confirmed the existence of 5hmC in the same issue of the journal.

Researchers consider 5mC a fifth base, and 5hmC a sixth base, of DNA, which is traditionally thought of as a string of four different chemicals called nucleotides. 5mC and 5hmC resemble the traditional base cytosine, but with a methyl group added on, making 5mC, and a hydroxy group added to the methyl, creating 5hmC. The new study confirmed that patterns of these chemical modifications to the genome are different in each cell and influence which genes are turned on or off and when.

The discovery of 5hmC opened up a new area of work—and hundreds of new papers—focused on where the nucleotide is in the genomes of different cell types, and what it’s doing.

In the new study, using an explorative molecular assay to fish for a binding partner for 5hmC, the group identified the molecule as MeCP2, and nothing else. “It was really a surprise,” Kriaucionis says.

“This paper is the second paper to suggest a candidate binding protein for 5hmC,” says Rao, now a professor of signaling and gene expression research at the La Jolla Institute for Allergy and Immunology, who was not involved with the new study. Other findings have proposed a different molecule, MBD3, as a candidate, but those and the new results need further investigation, she adds.

“So far, both candidates — MBD3 and MeCP2—also bind 5mC, so an exclusive binding protein for 5hmC has not yet emerged,” Rao says.

Indeed, contradicting the new evidence that MeCP2 binds 5hmC and 5mC equally, some previous studies show that MeCP2 much prefers binding to 5mC over 5hmC. For example, a study published earlier this year shows that says MeCP2 is nearly 20 times more likely to bind 5mC than 5hmC.

Relating to Rett

In the new study, Kriaucionis and his colleagues observed that a certain Rett-causing mutation, called R133C—which is responsible for a relatively milder form of the disorder—disrupts MeCP2’s binding to 5hmC.

“[The R133C mutation] is really interesting because it allows us to speculate that MeCP2 binding to 5hmC is important as a part of the function which causes Rett Syndrome,” Kriaucionis says.

The evidence now “strongly suggests” the potential involvement of 5hmC in Rett, says Peng Jin, an associate professor of human genetics who was not involved with the new study. A study his group published last year in Nature Neuroscience found that patterns of 5hmC are altered in mouse models of Rett.

Interestingly, the R133C mutation only slightly dampens MeCP2’s interaction with 5mC, suggesting that MeCP2’s binding with 5mC serves a different purpose than that of MeCP2 and 5hmC.

Other Rett-causing mutations in MeCP2 examined by the group don’t seem to affect binding to 5hmC, meaning 5hmC binding does not fully explain the symptoms of Rett.  “It will be important to test further the contribution of 5hmC to Rett Syndrome,” notes Jin, adding that there are mouse models available to do so. Those mutant mice lack the enzymes needed to convert 5mC to 5hmC.

In the new study, researchers studied only a few types of neurons, but there are hundreds of cell types in the brain. Kriaucionis thinks that MeCP2 binds to 5hmC in other cells.

The 5hmC patterns themselves are cell-specific, however, perhaps further complicating the story of MeCP2.

“We really need to get more data to understand whether or not, how different 5hmC and MeCP2 localization would be in different cell types,” Kriaucionis says. “It’s an important component to understand MeCP2 function,” and how scientists might think about future treatment.

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Cell podcast with Nat Heintz    (click on Paperclick on right)

HHMI Press Release

RETT SYNDROME RESEARCH TRUST WEBSITE

This week’s issue of Nature contains a provocative article (see below)  suggesting that the National Institutes of Health is missing the mark by funding “safe” science rather than novel and potentially game-changing research.  The claim is hardly new.  In fact scientists often joke that in order to get NIH funding one needs to have already completed the experiments and have data in hand.  The Nature article now backs up the charge with data of its own –  the majority of the nation’s most influential scientists are not receiving NIH funding.  Why this is happening may be easy to explain. How to fix it is likely to be problematic.

While this issue will be the topic of ongoing discussions for months and years to come at NIH, Congress and academic institutions around the country one thing is starkly clear: there is a great need for organizations like RSRT that do not shy away from high-risk projects.

nature

“Capecchi got the grant and put all the money into the part the reviewers discouraged. “If nothing happened, I’d be sweeping floors now,” he said. Instead, he discovered how to disable specific genes in animals and shared the 2007 Nobel Prize for medicine for it.”

“Conformity,” “mediocrity” win biomedical funding, say critics
By Sharon Begley for Reuters

NEW YORK (Reuters) – Accusations that the leading U.S. funders of biomedical research “ignore truly innovative thinkers” and “encourage conformity if not mediocrity” are seldom heard in the polite precincts of top science journals. Yet they are front and center in a paper published Wednesday in the journal Nature, which concludes that fewer than half of America’s most influential and productive biomedical scientists now receive funding from the National Institutes of Health.

Critics have long argued that NIH, which spends some $30 billion a year on biomedical research at universities and medical centers worldwide, funds conventional, incremental science rather than swing-for-the-fences studies more likely to produce breakthroughs. But the new analysis goes further: It marshals data to show that U.S. biomedical researchers who make the most influential discoveries are not getting NIH support.

“I was astonished” by the findings,” said Jack Dixon, vice president and chief scientific officer of the nonprofit Howard Hughes Medical Institute (HHMI), who was not involved in the study. “It’s just amazing that most of NIH’s $30 billion is going to scientists who haven’t had the greatest impact.” (continue reading on Reuters.com)

by Monica Coenraads

In January of this year a gentleman who has a granddaughter with Rett Syndrome introduced me to his neighbor, David Scheer, a 31-year veteran of the life sciences industry. I was eager to meet David, whose entrepreneurial focus lies at the intersection of finance and science. Our planned hour of conversation turned into a three-hour discussion as we delved into David’s network, experiences, and the potential synergies we might explore. Over the past 9 months I’ve come to rely on David’s insights, perspective and advice. I’m delighted that he has agreed to serve on RSRT’s Professional Advisory Council and look forward to working closely with him on our drug development strategies.

MC: David, please start us off by telling us a bit about your background.

DS: I began with an undergraduate degree in biochemical sciences from Harvard and went on to study cell and molecular biology and pharmacology at Yale. While in graduate school during the early 80’s, I started doing consulting work in the emergent fields of molecular biology and biotechnology. This became a life sciences consulting practice that brought together venture capital, transactional advisory services, and corporate strategy. Scheer & Company is best known for having launched a series of companies spanning the fields of infectious disease, cardiology, oncology, and neurology, to name a few. We’ve had some pretty significant successes among the entrepreneurial enterprises we have launched and built. One of our companies launched a product that was ultimately acquired by Johnson & Johnson; another, a company called Esperion Therapeutics, developed a product in HDL (good cholesterol) therapeutics which was sold to Pfizer in 2004 for $1.3 billion. In the roles of founder and director of numerous companies, I have been involved in identifying technology, recruiting people and raising capital. In most of my more recent companies, I have served as Chairman of the Board.

MC: David, one of your companies, Aegerion Pharmaceutical, operates in the ultra-orphan disease world. Can you tell us a bit about that company?

DS: Aegerion has developed a drug for a very rare disease present in only one in a million people: Homozygous Familial Hypercholesterolemia (HoFH). The disease causes very high bad cholesterol that confers high risk for cardiac events like strokes or heart attacks, even in individuals as young as teenagers, for those who are untreated. We are pursuing approval with both FDA and European regulatory authorities, and we have put in place management and commercial infrastructures in the US and Europe to make the drug available to patients in need, when there is the proverbial regulatory green light. As Chairman of the Board of this company, I have become quite interested in the area of rare diseases.

MC: Lately, pharmaceutical companies seem to all be starting rare disease initiatives. This is in stark contrast to the traditional focus on blockbuster and “me-too” drugs. What is driving this change?

DS: The traditional view has been if there are not enough patients, it’s not really worth developing a drug. However, pioneering companies such as Genzyme, BioMarin, and more recently, Alexion, have successfully developed life-saving drugs to treat rare diseases while providing a return on investment for their shareholders. In so doing, they have opened the eyes of people in the pharmaceutical industry. This shift holds clear potential for organizations working toward the development of therapies for rare diseases, such as the Rett Syndrome Research Trust.

I suspect that rare diseases may also provide an easier path for drug approval. Much of the cost of drug development comes at the end, during the extremely large and expensive clinical trials that are needed for blockbuster drugs. In the rare-disease space, due to the small population sizes, trials will be much smaller, and therefore less expensive. Also, the regulatory process may be fast-tracked for a rare disease, as the FDA recognizes the enormous unmet need and cooperates with sponsors and patient advocates to provide new agents sooner.

So interest in innovation in the rare disease category has turned bullish, which makes this an exciting time for someone engaged in your work, Monica, and frankly also for people like me who are really interested in efficient and effective development of new drugs.

MC: Are large pharmaceutical companies set up to tackle drug development for rare diseases?

DS: I think the answer depends on the drug company. The bulk of the rare-disease experience in drug development has traditionally come from innovative smaller companies. For example, Genzyme, which started off as an idea on the back of an envelope, became a multimillion-dollar pharmaceutical company with a large number of products in its portfolio, and was recently acquired by Sanofi-Aventis. Sanofi now has a franchise that is very capable and active in the rare-disease field. Other companies have either built from scratch, made smaller acquisitions, or are making partnerships or deals with companies that have assets or programs in rare-disease drug development. Pfizer and GlaxoSmithKline have done this, and both now have rare-disease units.
I think it is too early to predict the success of these larger companies. Can the big companies be as effective as some of the smaller companies have been? Will the entrepreneurial spirit of a Genzyme in the early days be retained or lost as part of a larger company? We shall see.

MC: How do FDA drug reviews for a rare disease differ from those for a common one?

DS: The FDA has really had to modify its approaches to adapt to the needs of the rare-disease community. In fact, there is an orphan-disease unit within the FDA that is specifically tasked to review rare-disease drugs. These people are very familiar with how to evaluate a drug through a very different lens than is ordinarily used. It is important to keep in mind that regulatory decisions are always based on a favorable risk-benefit relationship.

MC: The Rett community, including families, clinicians and researchers, is highly concerned—-and properly so—with rigorous validation of pre-clinical advances and the complexities of developing solid protocols for outcome measures. Though Rett patients are a small population, the range of symptoms is staggering, so there are many issues to address.

DS: There are no perfect drugs – even Tylenol can have dreadful side effects if taken in excess, such as liver failure. The FDA must balance the solemn task of making available new and important therapies, while ensuring that such agents demonstrate safety and efficacy commensurate with the condition being treated.

MC: You were only recently introduced to Rett. What have you found most interesting thus far?

DS: That it has attracted some very talented individuals. The scientists, thought-leaders, and patient advocates involved in Rett Syndrome research represent an incredibly impressive group. Perhaps this is because Rett Syndrome is believed to be scientifically very tractable. It certainly helps that it is a single-gene disorder. The number of chronic conditions that can be attributed to a single gene is relatively low. So if I may say this, those in need of therapeutics for Rett Syndrome, may be fortunate in that there is an important foundation for discovery of potentially novel, disease-modifying therapeutics.

MC: I think the 2007 proof-of-concept reversal has also helped put Rett on the map; it had been a much more obscure disorder before that breakthrough.

DS: I agree. Each year in my not-for-profit work, I organize and chair a conference in New Haven, in conjunction with Yale and the Long Wharf Theater, called Global Health and the Arts,. For the past four years, this conference has promoted examination of important disease topics in public health and global health. This past May, we explored the neuropsychiatric disease arena. We had a major scientific symposium, with some of the most well known academic and industrial thought leaders from around the world, who were able to give us an update on relevant areas of science and technology, drug development, genetics, genomics, and translational medicine. In the middle of this event we actually had several individuals comment on the importance of the work being done in Rett and related disorders.

Monica, you need to continue doing what you do so well: ensure you have the best information from scientists at the cutting edge of this field, and then position that knowledge in a way it can be most effectively translatable. The more quickly drug development gurus can bring their expertise to the table, the better the chances of a successful outcome. I am very much looking forward to help you achieve that success.

MC: Thank you, David, and on behalf of every Rett family, welcome.

RETT SYNDROME RESEARCH TRUST

Ever wondered why most labs use male Rett mice for their experiments even though the females are the better model? What human symptoms are replicated in the Rett mice? What are some of the surprises these mice have in store for us? What are the complexities of doing well-designed and executed trials in mice? What are some of the pitfalls that the Rett field needs to avoid? What is the potential for the newly unveiled Rett rat? Listen and find out….

Rett Syndrome Research Trust Website

by Monica Coenraads

It would be difficult to overestimate the importance of what we have learned from the mouse models of Rett Syndrome.  After all, without them we would not know that Rett is reversible.

It may come as a surprise that there is no single mouse model of Rett but rather a variety of genetic models, from “KO” or “knock-out” mice, which have no MeCP2 at all, to those in which the precise MeCP2 mutations that are seen in humans suffering from Rett Syndrome have been duplicated.

Jackson Laboratories in Bar Harbor, Maine currently distributes almost a dozen mouse models of Rett. Jackson (or Jax, as most scientists refer to it) is a non-profit organization that specializes in this work to advance the understanding of human disease. Although no animal model perfectly capitulates human symptoms or responses, 95% of our genomic information exists also in rodents. Maintaining an extraordinary level of care and attention to detail in this sensitive field, Jax conducts its own research as well as breeding and managing colonies of thousands of models.

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To learn more about Jax please read an earlier blog post, Of Mice and Men…Or in the Case of Rett…Of Mice and Women.

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Having access to the various models of Rett Syndrome is crucial to the advancement of research and this is an area that RSRT and its predecessor, RSRF, have been actively involved in since the first animal models were published in 2001 by RSRT Trustee and advisor, Adrian Bird and by Rudolf Jaenisch.

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From the Jax website:  “Partners in the fight against Rett syndrome,” a story about how Monica Coenraads, the mother of a daughter with Rett syndrome and co-founder of two organizations focused on treating it, is working with Dr. Cathy Lutz to develop and distribute new mouse models of Rett syndrome.

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Sharing mouse models is not always the norm as this article about a mouse model for Angelman Syndrome illustrates. We are extremely fortunate that researchers in the Rett field have been stellar about quickly sharing their models. Adrian Bird, Rudolf Jaenisch and Huda Zoghbi have set an exemplary high bar when it comes to making their own mouse models available as soon as they publish.

In some cases sharing the mouse has even preceded publication. Last year Nature reported on a situation regarding a Rett mouse that had been developed by Novartis. The model had been engineered so the Rett protein glowed so it could be tracked visually.  Many researchers were eager to access the model but could not due to legal issues. (Nature article – Licence rules hinder work on rare disease.  Animal model off-limits to Rett syndrome researchers.)  I knew that Adrian Bird after being denied access had created his own model and I asked him whether he would be willing to share it through Jax. He agreed immediately even though he had not published yet. The mouse is now available to any researcher worldwide that needs it.

Besides teaching us about the molecular underpinnings of disease, mouse models may be effective to test treatments.  We have all heard many stories about how drugs tested in mice with success are found to be ineffective in humans. The next few years will be extremely interesting as we begin to explore how predictive the Rett mice models really are.

Rett Syndrome Research Trust Website

Adrian Bird and colleagues recently published  their latest paper on MeCP2 in the journal Human Molecular Genetics. The series of experiments described in the paper were designed to explore what happens when the MeCP2 protein is removed from mice of various ages, including in a fully adult mouse. This work was funded in part by RSRT with generous support from RSRT UK, Rett Syndrome Research & Treatment Foundation (Israel) and other organizations who financially support our research effort.

Below are excerpts from a conversation with joint first authors Hélène Cheval and Jacky Guy.

Jacky Guy (far right), Hélène Cheval (2nd from right) with Adrian Bird and other lab members. University of Edinburgh, Scotland

MC  Dr. Cheval, you trained as a neuroscientist. What attracted you to the Bird lab, which is very biochemistry-based, and where you are the sole neuroscientist?

HC  My previous lab, run by Serge Laroche,  was a pure neuroscience lab focused on learning and memory. However, I was actually doing biochemistry and I was very much interested in how to get from molecule to behavior, and I was also quite interested in chromatin.  I had read the Bird lab reversal paper of 2007 and thought it was one of the most exciting papers I had ever seen. Upon receiving my PhD I applied for a post-doc position, convinced that it would be a great experience for me but also thinking that perhaps the lab would benefit from having someone with a neuroscience background.  I joined the lab in 2009.

MC  Dr. Guy, you co-authored your first paper on Rett Syndrome in 2001. That was the paper that described the MeCP2 knockout mouse model made in the lab, one that is now used in hundreds of labs around the world.

JG  I joined the lab in 1997. My first project was to make the conditional mouse models of Mecp2, meaning mice where the protein can be removed at will.  At that stage we didn’t yet know about the link between MECP2 and Rett Syndrome.  That came about as I was working on the project. It was a very exciting time.

MC  It’s unusual for people to stay in a lab so long. This gives you an amazing depth of uninterrupted knowledge about the field.

JG  I took a rather unconventional path. I’m very happy to do bench work and being able to work in the same field has been wonderful.

MC  Dr. Guy, perhaps you can start us off. What are the key questions you were trying to answer with this series of experiments?

Jacky Guy

JG  This was actually an experiment we had been wanting to do for a long time.  We have always been interested in defining when MeCP2 is important.  Rett had been thought of as a neurodevelopmental disease. Since we were completely new to Rett, we thought maybe it’s not neurodevelopmental. So we set out to remove the protein at different ages and see what happens.  Removing the protein is not quite as simple as reactivating the gene, which we had already done in the reversal experiment. When you reactivate the gene it makes protein right away. In this experiment, however, when you deactivate the gene you have to wait for the protein to decay away. We found it takes about two weeks for the amount of MeCP2 protein to fall by half.

HC  Jacky’s reversal experiment suggested that MeCP2 is implicated in adulthood. But many papers were still describing Rett as a neurodevelopmental disease.  We also wanted to confirm a hypothesis that we all shared in the lab that MeCP2 is required throughout life.

MC  That is a hypothesis that was also put forth in Huda Zoghbi’s 2011 Science paper. She showed that removing Mecp2 in adult mice aged 9 weeks and older caused Rett symptoms. Do you think that her paper and your new data have definitively put to rest the notion that Rett is neurodevelopmental?

HC  To my mind it’s clear that it’s not merely neurodevelopmental.

JG  I think “merely” is the key word here. The phenotypes we analyze in mice are those that are quite easy to see; for example, lifespan, breathing, gait. There might be more subtle things that we are not observing, or that are not affected by knocking out the protein in adulthood.  And we are not analyzing cognitive aspects. So we can’t completely rule out the possibility that there could be some things that are indeed of a neurodevelopmental origin that we are not seeing in these experiments.

JG  Mecp2 can be deleted by treating the mouse with tamoxifen in the same way the protein was reactivated in the reversal paper.  In this paper we picked three different time points to turn off the gene: three weeks (which is when mice are weaned and begin to live independently) eleven weeks and twenty weeks.   In all three scenarios the tamoxifen was able to delete Mecp2 in about 80% of the cells.

What you might expect is that at whatever age you delete the gene, there will be a certain amount of time for the protein to disappear and then the effects of not having the protein will appear.

In fact, what we found is that the time it took for symptoms to appear varied with the age at which we inactivated the gene.  It took longer for the symptoms to appear when we deactivated Mecp2 at 3 weeks.  When we removed MeCP2 in older mice, the symptoms appeared more rapidly.  So it seems that younger mice are able to live symptom-free without MeCP2 for a longer period of time. There is a certain period when the need for MeCP2 becomes more important in mice. This is the first critical time period that we talk about in the paper; it happens around eleven weeks.

Drs. Cheval and Guy with Prof. Bird and other lab members

As we followed the mice treated at all three time periods, eventually they all started to die at about the same age, approximately thirty-nine weeks, regardless of when MeCP2 was removed. We concluded that this time period centered around thirty-nine weeks represented a second critical period for MeCP2 requirement. This is a time in a mouse that roughly coincides with middle age in humans. We think that maybe MeCP2 is playing a role in maintaining the brain as it ages.

Interestingly, this time frame of thirty-nine weeks is when female mice that are MeCP2-deficient in about 50% of their cells from conception begin to show symptoms. The male mice which have zero MeCP2 can’t make it past the first critical time period of eleven weeks. When you delete MeCP2 in 80% of the cells, the male mice show symptoms at 11 weeks and die at 39 weeks. So having about 20% normally expressing cells allows you to survive the first critical period but not the second.

MC  I’ve heard clinicians say that women with Rett in their 30s and 40s and beyond look older than they are. I wonder if this has anything to do with your hypothesis that MeCP2 may play a role in aging. Of course we don’t know if the premature aging is primary or secondary.  It may have to do with the effects of dealing with a chronic illness for many years.

JC  We are quite interested to learn about  a potential late deterioration in women with Rett but there is very little published on the subject.

MC  There are two potentially critically relevant points made in your paper. One is the fact that the half-life of the MeCP2 protein is two weeks. That could be relevant and encouraging for a protein replacement approach.

JG  We certainly had this in mind when we were doing the experiment.  The half-life of MeCP2 is longer than we expected. And could in fact bode well for protein replacement therapy. One caveat, ours was a bulk brain experiment. It could very well be that if you looked regionally in the brain or by cell type you might find varying results.

MC  The other potentially clinically relevant information comes from comparing the severity of symptoms seen in the mice in this study versus the adult knockout done in the Zoghbi lab and correlating symptoms to amount of MeCP2 protein. Your experiments yielded 3% more protein and resulted in less severely affected animals. Can you elaborate?

HC   That such a small difference in protein could have such a significant impact on survival is unexpected and indeed may be relevant for therapeutic interventions. We may not need to get the protein back to wildtype levels to have an effect. It may be possible that even small increases may be helpful.

MC  Congratulations to you both on this publication. The Bird lab has made numerous seminal contributions to the Rett field. The Rett parent community doesn’t typically have a chance to glimpse the researchers behind the experiments, doing the day-to-day work, so I’m delighted to provide an opportunity for our readers to get to know you a bit.  I look forward to the next publication. Best wishes for your ongoing work.

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P
hotos courtesy of Kevin Coloton

RETT SYNDROME RESEARCH TRUST WEBSITE

Last month brought me to Houston, Texas to attend a fascinating meeting organized by Huda Zoghbi and Morgan Sheng and co-sponsored by RSRT. Entitled Disorders of Synaptic Dysfunction, the event was the inaugural symposium of the recently established Jan and Dan Duncan Neurological Research Institute, directed by Dr. Zoghbi.

The two-day meeting brought together a heterogeneous group of scientists from academia (senior and junior faculty as well as post-docs and graduate students), industry, NIH and other funding agencies.

The focus was not on  a single disease but rather on a group of disorders (Rett, Angelman, Fragile X, autism, Tuberous Sclerosis) that share a common cellular phenotype: abnormal synapse activity.

It’s no surprise that some of the talks that generated the most buzz came from labs that are doing very clinically relevant research. These include the labs of Mark Bear at MIT, working on Fragile X, and Ben Philpot at UNC whose lab works on Angelman Syndrome.

Like Rett Syndrome, Fragile X is a single gene disorder, caused by mutations in a gene called Fmr1. When Fmr1 is mutated, protein synthesis fails to shut down, leading to excess. Some years ago Dr. Bear proposed that compounds which can block a certain type of receptor, mGluR5 (which triggers the burst of synaptic protein synthesis) might counteract over-expression of protein and thereby cancel out the damaging effect of Fmr1 deficiency. His theory has proved correct, and clinical trials of mGluR5 antagonists are currently ongoing at multiple pharmaceutical companies.

I first met Dr. Bear almost a decade ago, when he was just beginning to formulate what is now commonly known as the mGluR5 theory of Fragile X.  His lab is currently funded by RSRT to explore protein synthesis in the Rett mouse models. Dr. Bear hypothesizes that Rett may be due to under-expression of proteins. If his hypothesis holds up, pharmacological manipulations of mGluR signaling will be pursued.

Ben Philpot’s talk also generated excitement. He discussed a high-throughput screen that has yielded a compound which can activate the silenced Angelman Syndrome gene, UBE3A. Dr. Philpot is currently funded by RSRT to pursue a similar approach for the silent MECP2 gene on the inactive X chromosome.

Mike Greenberg spoke about MECP2 and shared unpublished data that has come about from his collaboration with Adrian Bird via the RSRT funded MECP2 Consortium. (More on that in the months to come.)

Jackie Crawley of the NIH gave a brilliant talk on how “autistic mice” are being characterized to yield a plethora of new information.  For me the highlight of her talk was hearing recordings of mouse “speech”. She shared a variety recordings and I was taken aback by the complexity and richness of the sounds, which left me yearning for an analysis of Rett mouse vocalizations.

After a lively cocktail hour it was back to work with dinner plates in hand. Drs. Zoghbi and Sheng divided the attendees into three working groups: 1) dysfunction of proteins of the synapse 2) dysfunction of nuclear/cytoplasmic proteins 3) young investigators and junior faculty.  Masquerading as a 30-something I happily joined the third group.  I was struck by the fearlessness and boldness of these young scientists. There were not shy about criticizing the status quo and what could be done differently to enhance the research progress. I came away feeling buoyed and reassured that science is in good hands with this new generation.

The following several hours of discussion, led by Rodney Samaco and Mingshan Xue and facilitated by NIMH Director, Tom Insel, were intellectually stimulating and entertaining. Below is a visual output of our intense discussion.

A few personal reflections on the symposium

  • Over and over again throughout the meeting I heard comments from autism researchers such as: “Where would we be without the syndromic autism animal models like Rett and Fragile X? We’ve learned so much from them”.  More than once I found myself thinking that as horrible as Rett is at least the genetics of the disorder are clear-cut – Rett’s silver lining.
  • The meeting provided an opportunity to meet some scientists with whom I had communicated by email and/or phone, but never met in person. People like Pat Levitt, Freda Miller and Michael Palfreyman.  It was a reminder of how many people over the years have taken the time to discuss their work and possible synergies to Rett Syndrome.
  • Drs. Zoghbi and Sheng kept everyone busy from the moment the meeting started to the moment we left, including an intense working dinner. I tend to do the same thing  at meetings that I organize, but always feel like I’m being a bit of a slave driver. Never again, however, will I feel guilty. If Dr. Zoghbi thinks it’s acceptable, then so do I!

Kudos to Drs. Zoghbi and Sheng for a stimulating meeting and thank you both for inviting me.

Science Translational Medicine, which co-organized the meeting, will be publishing a white paper on the proceedings.
RSRT will let you know when the paper is available.
RETT SYNDROME RESEARCH TRUST WEBSITE

The recent publication of the Kipnis paper in Nature has generated understandable excitement and questions in the Rett community. Email and Facebook are difficult vehicles for providing proper answers. Rett Syndrome is complex, and so is the research; this work doesn’t lend itself to sound bites. I know Rett mothers and fathers are often tired and overworked, but I encourage you to find fifteen minutes to sit down together with a cup of coffee, listen carefully to what these researchers are discussing in the video interview, and come away more deeply informed.

The paper has already been euphemistically coined the bone marrow transplant paper. I’ve occasionally called it that myself, sometimes in the presence of Dr. Kipnis, who promptly says, “Please don’t call it that. There is so much more information in that paper than just the bone marrow experiments.” He’s right. In fact, there is enough material to have generated multiple publications.

The paper is attracting an unusual amount of attention in the scientific community, and this is bound to stimulate more interest in Rett Syndrome and the role of the immune system in neurological disorders. The bone marrow transplant result is understandably what families gravitate to because of the potential for clinical application, but it’s important not to ignore the other findings, because they too could point to eventual treatments. In fact, it is my fervent hope that in time, new discoveries will make it possible to manipulate the immune system through a safer route.

Bone marrow transplants (BMT) have been used since 1968 to treat an increasingly wide range of disease, including cancers, metabolic diseases, inherited red cell disorders and immune disorders. The treatment can be lifesaving. It can also be fatal. Accompanied by chemotherapy and/or radiation treatment, BMT is a serious and grueling procedure with significant side effects. The combined expertise of specialists in pediatric BMT, as well as in Rett Syndrome,  together with basic scientists is crucial to minimizing risk as much as possible.

As part of a fact-gathering process, RSRT has been facilitating talks between top pediatric transplant centers and Sasha Djukic, Director of the Rett Syndrome Center at the Children’s Hospital at Montefiore, Jonathan Kipnis and his lab members and, most recently, NIH. Discussion includes defining the data needed to consider clinical trials. This must be completed and thoroughly evaluated in order to design the best possible treatment protocol. Independent confirmation of the results achieved by Dr. Kipnis and his team is a standard requirement; this work is already underway. Further experiments in the Kipnis lab itself are ongoing, and we can expect more new information to emerge.

It is perhaps timely for me to reiterate that RSRT is very aggressive about research, and conservative about clinical application. I want to be crystal clear on one thing – parents should not take it upon themselves to pursue BMT for their child. As the mother of a severely afflicted daughter, I understand all too well the desperation for treatment. As Executive Director of RSRT, I understand equally well the importance of applying meticulous due diligence. RSRT does this in all the work we undertake, the projects we review, our financial decisions, and certainly in our approach to clinical trials.

I share your excitement, your urgency and your trepidation, and RSRT will continue to inform you of new developments as they unfold.

– Monica Coenraads
Executive Director, RSRT

RETT SYNDROME RESEARCH TRUST WEBSITE

Click Here to Read Press Release

A paper published online today in the high-profile journal, Nature, describes the results of using a bone marrow transplant to dramatically stop the development of symptoms in pre-symptomatic male and female mouse models of Rett Syndrome.  The work was undertaken in the neuroimmunology laboratory of Jonathan Kipnis, Ph.D. and his team at the University of Virginia.

That a bone marrow transplant could arrest such a severe neurological syndrome such as Rett is quite unexpected and provides us with yet another strong example of how tractable this disorder appears to be – at least in the animal models.   Experiments are now underway in the Kipnis lab to test whether reversal of advanced symptoms via bone marrow transplants and other modulation of the immune system is also possible.

This work was funded by the Rett Syndrome Research Trust and the Rett Syndrome Research Trust UK.

Jonathan Kipnis and Noël Derecki

Jim Cronk and Noël Derecki

The clinical relevancy of this work makes this paper of obvious and significant interest. But the authors don’t stop there. The paper describes data that could help us better understand how MeCP2 deficiency leads to symptoms.  They introduce the concept of a powerful connection between the immune system and Rett Syndrome and open the door not only to bone marrow transplants as a treatment modality but potentially to other immune therapies as well.

To help you understand the key findings and implications we invite you to watch the videos below. Please watch the animation of the experiments first followed by the interview.

We would like to take this opportunity to thank Jeff Canavan of NewsAnimation for volunteering his time and effort to create the beautiful animation below. Jeff has a daughter with Rett Syndrome and founded, with his wife Sarah, the Kate Foundation for Rett Syndrome Research.

ANIMATION OF EXPERIMENT

We thank Jeff Bemiss for donating his filmmaking expertise, substantial time, energy, equipment and editing resources to film the interview below. He comes to our cause through his friendship with the Canavan family.

INTERVIEW WITH RESEARCHERS