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.
Brenna and Mike Johnson of Tustin CA were devastated when their daughter Gisele was diagnosed with Rett last fall. But the Johnsons quickly got to work to make a difference to the research that they know will change Gisele’s life. In early December they started an online campaign for RSRT using FirstGiving.com. They called it A Cure for Christmas, and their friends, colleagues, and family came out in full force to contribute to RSRT’s research program. So far they have raised almost $60,000, a record for an online campaign for RSRT. Mike added further interest by swearing off shaving during the campaign, although their friends and family were so quick to support the cause that his beard didn’t even get very long. As Brenna says, “we were overwhelmed by everyone’s generosity and eagerness to be a part of this; and we’re proud to be helping RSRT move the science forward.” Hearty congratulations and thank you from RSRT to Brenna and Mike and all their network of supporters. Starting a fundraising campaign on FirstGiving.com is easy and effective. Contact Tim Freeman at RSRT if you have questions or need help, email@example.com or 609.309.5676.
Highlights of RSRT’s 2014 awards:
- Funding of $1.3 million was awarded to Case Western Reserve University and the Cleveland Clinic for a Phase 2 clinical trial of low-dose ketamine for the treatment of Rett Syndrome. Ketamine, a drug that has historically been used for sedation and anesthesia, has recently generated much enthusiasm for its ability to rapidly reverse major depression at low, sub-anesthetic, doses. Studies undertaken by David Katz, Ph.D., showed that low-dose ketamine can reverse deficits in brain activity in mouse models of Rett Syndrome in conjunction with significant improvements in neurological function, including breathing. This trial will determine the effect of single doses of ketamine on breathing abnormalities and other Rett Syndrome symptoms.The study is being led by David Katz, Ph.D., Professor of Neurosciences and Psychiatry at Case Western Reserve University School of Medicine and Daniel I. Sessler, M.D., Michael Cudahy Professor and Chair, Department of Outcomes Research at the Cleveland Clinic.
“This trial evolved as a dynamic collaboration among basic scientists, clinicians, and clinical trialists including expert advisers recruited by RSRT. We are grateful to RSRT for fostering this collaborative spirit and providing the support necessary to make this trial a reality.”
- Aleksandra Djukic, M.D., Ph.D., medical director of the Tri-State Rett Syndrome Center at the Children’s Hospital at Montefiore was awarded $403,000 to conduct a Phase 2 clinical trial of lovastatin, a cholesterol lowering medication. The scientific basis for this trial stems from experiments conducted in the lab of mouse geneticist, Monica Justice, Ph.D., who identified the cholesterol pathway as a potential avenue to improve Rett symptoms. The trial will determine the effect of lovastatin on gait, respiratory function, cognition and other Rett symptoms including the severity of the disease.In addition, Dr. Djukic recently concluded a Phase 2 trial testing safety and effectiveness of a multiple sclerosis drug, copaxone, in treating Rett Syndrome. The data is currently being analyzed.
“Cholesterol is vitally important for brain function. In fact, although the brain is only 2-3% of total body weight, it contains and makes 25% of the body’s cholesterol. Dr. Justice’s work suggests that elevated cholesterol levels in the brain may play a role in Rett symptoms. Our trial will test the hypothesis that reducing cholesterol in the brain will lead to symptom improvement.”
The ketamine and lovastatin trials will begin recruitment shortly. We will send you notification as soon as they are ready to proceed and will provide detailed information on the RSRT website.
- Individuals with Rett display a broad spectrum of symptom severity. Some girls can run, have a degree of hand use and can speak in short sentences while others cannot even sit or hold their head up. One reason for this variation is the child’s own unique genetic makeup. In other words, we’ve learned that variations in other genes have an impact on the severity of the Rett mutation. Monica Justice, Head and Senior Scientist in the Genetics & Genome Biology program at The Hospital for Sick Children in Toronto, has undertaken a screen to identify these other, modifying genes that potentially impact the severity of Rett symptoms. The first suppressor gene she identified, squalene epoxidase, led to the lovastatin trial described above. The screen is currently at the halfway point, with 12 modifiers identified. RSRT has awarded Dr. Justice $716,000 in additional funding to complete the screen. This brings RSRT’s total commitment to the project to $2.3 million.
“Monica Coenraads approached me a number of years ago asking how I would identify modifiers. I thought that an unbiased suppressor screen using a mouse supermutagen would be the most effective approach, and was timely with the advent of new genome sequencing technologies. Such an approach was considered very risky, requiring funding through a forward-looking organization such as the RSRT. It has been extremely rewarding to move from the development of a concept…to isolating modifiers that were unexpected…to a clinical trial. Our ongoing screen is much easier and quicker now as technologies advance. My hope is that many more trials will come from the continuing screen.”
- Two additional projects are aimed at awakening a healthy but silenced back-up copy of the mutated Rett gene. If the flawed gene could be replaced by reawakening its silenced counterpart we could conceivably reverse Rett symptoms.Currently pursuing this approach with RSRT funding are labs at the University of North Carolina at Chapel Hill, the University of Massachusetts, Harvard University, and Fred Hutchinson Cancer Research Center. These labs are now in regular communication because of RSRT’s strong belief in and facilitation of collaborative research models that encourage the sharing of data, cell lines and compounds.RSRT has awarded additional funding totaling $755,000 to two projects ongoing in the labs of Jeannie Lee, Ph.D., of Harvard and Antonio Bedalov, M.D., Ph.D., of Fred Hutchinson to aggressively pursue this work.
- RSRT funding will allow David Katz to purse research on the drug, LM22A-4, towards an application to the FDA for an IND (Investigational New Drug).
- Successful fundraising on the part of the MECP2 Duplication Syndrome community facilitated two awards totaling $644,065 to Huda Zoghbi, M.D., Professor in the Departments of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience at Baylor College of Medicine and director of the Jan and Dan Duncan Neurological Research Institute. The funds will support two strategic approaches to treating the disorder.
“We are very excited to receive support for exploring two different strategies to reduce MeCP2 levels. The two strategies are complementary, one involving genetic screens in human cells to find potential targets that can be druggable with a pharmaceutical agent, while the other employs antisense oligonucleotides developed by Isis pharmaceuticals and designed to reduce MeCP2 levels directly.”
Our partners in supporting this work are parents’ organizations worldwide including Reverse Rett (UK), Rett Syndrome Research & Treatment Foundation (Israel), Skye Wellesley Foundation (UK), Rett Syndrome & CDKL5 Ireland, Rett Syndrom Deutschland, Stichting Rett Syndrome (Holland); and American organizations, Girl Power 2 Cure, Eva Fini Fund at RSRT, Kate Foundation for Rett Syndrome Research, Rocky Mountain Rett Association, Anastasi Fund, Claire’s Crusade, New Jersey Rett Syndrome Association, Rett Syndrome Association of Massachusetts, and the MECP2 Duplication Syndrome Fund at RSRT.
Guest Blogger Beth Jones, whose daughter Jocelyn has Rett Syndrome, urges more families to take action
Yesterday, we sat in 5 hours of traffic taking Jocelyn to Los Angeles for her orthopedic appointment. Her scoliosis is turning her into a question mark, her back brace is so uncomfortably tight it disturbs her g-tube and makes feedings difficult. We strive to do the best for our daughter but we are constantly juggling details like this. After the long day, the-oh-too-familiar feelings of “defeat” and “alone” swarmed over me. A feeling I am certain every Rett Syndrome parent feels from time to time.
But today is a new day. Today I am preparing for our first committee meeting of the year for Jocelyn’s Journey. Today, I get to fight back and drink up the hope that once Jocelyn is cured, days like yesterday will be a memory, instead of my day to day reality.
This is our 5th year hosting Jocelyn’s Journey and we’ve proudly supported the Rett Syndrome Research Trust with 100% of the revenue from each event. As I reflect on our first year hosting, I was a mess, honestly. It was hard for me to admit that I needed help. I was so afraid no one would buy tickets to come to our event. I was worried what people would think of me, asking for money. I was worried my friends and family would be too busy with their own lives to join forces with me and make a committee. I have learned, in the past five years, that I couldn’t have been more wrong.
The outpouring of people who support us each year has humbled us. I’ve learned that people want to help us, they just don’t know how. Having an annual event that supports the research that will one day CURE Jocelyn inspires and thrills everyone to help. Our committee has grown from 5 people to 20 in just a few short years! We sell out of tickets each and every year for the event, donations roll in and we are becoming well known around our community. RSRT is very helpful each and every year and has guided us on what to do, as I had NEVER done anything like this before. Year one, left me hooked—I figured out how to get over the sadness, defeat, feeling alone and helpless: I fight back! Jocelyn’s Journey’s moto: “No donation is too small or too large” and we stand on that! We are grateful for every dollar and I know RSRT is too!
A few months ago, I was speaking to Tim Freeman, Program Director at RSRT, and he expressed to me “if just 10 more families would do what you are doing with fundraising, it would change the research”. I was sad that money was standing in the way of Jocelyn and all Rett girls getting treatment. But then I was excited—this was in our control! We, all Rett families, can fix this problem and expedite treatment!
The Jocelyn’s Journey committee and I have set a goal this year to be one of those 10 families by doubling our average fundraising earnings. So that leaves 9 families! There has to be someone out there who has thought of hosting an event but has been worried about how to get started. I relate to the hesitation, but be assured, you will have more support and guidance than you would expect. Call Monica or Tim, please! An event is absolutely worth it and brings in the most funding. An event can be anything you want it to be—a barbecue, a poker party, a pancake breakfast, a 5K walk or run. And there are other things you can do too. I did an “informational” booth at church to talk about Jocelyn and without asking, people handed over donations! Be creative, be fun! If all 15,000 Rett families hosted something small that raised just a few hundred to a thousand dollars, the impact would be huge. No event is too large, or too small! Please learn from my fear in the beginning: your friends and family want to help you—they just need you to give them the opportunity to help.
As Rett parents we know, the first step is the hardest one. Some of us, like myself, are still waiting to see their girl take her first step. The same holds true for fundraising—getting started is the first step and the hardest part. Once you get going though, you don’t want to stop. I won’t stop, I will not give up. I don’t expect Jocelyn to give up and I owe her the same strength in return.
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.
Recently I posed a few questions to the three investigators about the important work they are tackling.
Despite 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.
It’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.
It 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.
If 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.
I 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.
The 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.
Science 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.
It 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 Mandel 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|
|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!|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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!
|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.|
|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
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
The 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.
Stop Subsidizing Big Pharma
by Llewellyn Hinkes-Jones
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.
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
I am delighted to give you a brief update on the MECP2 Gene Therapy Consortium, the collaboration of four elite labs that RSRT launched earlier this year. As you know, the Consortium is charged with developing gene therapy techniques that could treat or significantly reverse the symptoms of Rett. Our goal is to get to clinical trials. The project is grounded in work done last year by Consortium members Gail Mandel and Brian Kaspar that showed for the first time reversal of Rett symptoms in mice using gene therapy techniques that have the potential to be used in humans. The reversal of symptoms in mice was quite remarkable, but there are many challenges to translating that to a reversal in girls and women with Rett. The Consortium is attacking these challenges head on.
Earlier this month members of the Consortium met in the boardroom of a JFK Airport hotel in New York (we did not want to waste any of our meeting time traveling to and from a hotel in Manhattan). In addition to Gail Mandel, other members of the Consortium are Stuart Cobb (University of Glasgow), Steven Gray (University of North Carolina at Chapel Hill), and Brian Kaspar (Nationwide Children’s Hospital). The Consortium has a timeline of 3 years and a budget of $1.5 million. RSRT hosts in-person Consortium meetings twice a year as well as regularly scheduled conference calls.
The advantages gained by labs working collaboratively are clear: speed (four labs contributing to the work that has to be done), real time sharing of information means more brainpower and broader perspectives for problem solving. This is an obvious example of more heads are better than one.
Three facts make Rett Syndrome an attractive disease for gene therapy: it is monogenic; it is remarkably reversible in animal models; delivering MECP2 does not require understanding its function.
There are several hurdles to overcome. There is a requirement for MECP2 in every part of the brain so the gene will need to be broadly delivered. Also, the MECP2 Duplication Syndrome suggests that too much MECP2 is bad. It is difficult in gene therapy to regulate how many copies of a gene enter a cell and how much protein is made so the issue of MECP2 dosage must be carefully explored. We know that having too much MECP2 from conception and through early development causes serious symptoms. But does the same hold true if extra MECP2 is delivered later in life? Also, is it possible that females tolerate greater amounts of this protein than males? These questions must be answered before a clinical trial can be proposed.
Consortium members are also working on the following key issues:
1) Vector optimization – The vector is the Trojan horse that delivers the gene into a cell. There are many types of vectors in use and many more under development. For Rett we need a vector that can get into the brain and spread efficiently throughout the organ. The delivery route will affect the vector of choice. For example, if you deliver intravenously (via the blood stream) there is concern that a large amount of vector will end up in the liver potentially causing toxicity. To get around this problem a vector that de-targets the liver would be very useful. If dosage of MECP2 turns out to be problematic vectors that can be turned off will be required.
2) MEPC2 optimization – There are limits to the amount of DNA that can be packaged into a vector. The entire MECP2 gene does not fit. Scientists therefore have to select the parts of the gene they think are the most important. In essence they need to design a “mini-MECP2 gene’. Similar “mini-gene” work is also underway in the lab of Adrian Bird and will be shared with the Consortium.
3) Delivery route optimization – Gene therapy can be delivered via the blood stream, intrathecally into the spinal cord (like an epidural), or directly to the brain. Each route has its own advantages and disadvantages.
4) Optimizing how much gene therapy to deliver – the scientists are delivering low, medium and high dosages in an attempt to see how much is needed to get a therapeutic effect without generating toxic side effects.
We thank our precious donors who make this critical research possible!
In Their Own Words
It is very stimulating to be part of such a focused group of experts on gene therapy approaches towards Rett. The previous studies that we performed in collaboration with the Kaspar group were promising in showing that expression of a good copy of MeCP2, delivered systemically with AAV9, ameliorated Rett-like symptoms in female mice and prolonged survival significantly in affected males. Most surprisingly, but importantly, although we did not achieve a large amount of expression of the good MeCP2 in brains of the treated mice, we still saw behavioral benefits. We are now trying to improve the expression level of delivered MeCP2 by redesigning the vector, according to ideas and experimental results presented at the Consortium meetings. The openness of the investigators propels our studies and makes for a productive venture that would not be possible by any one individual laboratory. Additionally, it saves time because we can move on from doing obvious experiments that were done already in another laboratory. Finally, for those crucial experiments that had positive results, we have the ability to reproduce them in a different laboratory to insure that the results are solid.
- Gail Mandel
The Kaspar Laboratory is extremely excited about the potential to deliver gene therapies to the CNS. We are encouraged with our delivery studies to target cells efficiently in the brain, where one requires the proper expression of MECP2. Furthermore, our clinical trial in Spinal Muscular Atrophy has to date demonstrated the safety of this gene therapeutic in children which is excellent news for development of gene therapeutics in diseases, such as Rett. As a laboratory, we have bolstered our Rett efforts and are making great progress in testing the safety and developing the pre-clinical data necessary for developing a treatment. Our approach is building off the success of our collaboration with Dr. Gail Mandel. We are thankful for her continued support on our steep learning curve of Rett. This Consortium allows us to learn from each other’s studies. It’s a great group of scientists and I’m privileged to be a part of it. I see the progress we are collectively making and the commitment to the development of a therapy for Rett patients. The path is starting to look much clearer to get there.
- Brian Kaspar
The Cobb lab shares Brian’s excitement about the consortium’s efforts and the potential for gene therapy to counteract the root cause of Rett Syndrome. The project is progressing on multiple fronts from vector design/optimization to assessing best delivery methods and testing for efficacy and safety. Whilst the concept of gene therapy is a very simple one, the route to developing a safe and effective therapy is not at all straightforward. A key element of the consortium is that it enables us to share ideas and to discuss and act on emerging results from the four labs in real time. This will inevitably lead to more rapid progress in addressing the various challenges. As well as coordinating efforts, the consortium also enables us to cross validate key experiments to ensure findings are robust and reproducible across laboratories. After our Consortium meeting Kamal and I traveled to visit Steve Gray’s lab at UNC Chapel Hill. It was an extremely valuable few days as we were able to not only observe but also practice various delivery route methods. We also were able to compare and standardize how we score neurological features seen in the mice. Spending time together also provided an opportunity to further discuss vector development. Our trip to the US for both the Consortium meeting and visit to UNC was very productive.
- Stuart Cobb
Our efforts to treat Rett syndrome are built on 7 years of experience with the Rett community along with “bench to bedside” approaches that we are taking for six other inherited diseases. Our gene therapy clinical trial for Giant Axonal Neuropathy laid an important foundation for a similar approach to be taken with Rett syndrome. Gene therapy for Rett is an enormous challenge, but the last few years have garnered a great deal of excitement based on the similar positive findings published by all 4 laboratories in this consortium in 2 seminal papers. We are excited to be part of this group, and together we can accomplish much more than my lab alone. When Dr. Cobb visited our lab recently he provided critical expertise in a short visit that saved us an enormous amount of time and effort if we had been working alone. This is a small example of the many benefits we have had from working together in a collaborative fashion.
- Steve Gray
I’ve been thinking a lot lately about the phenomenon of the Ice Bucket Challenge that swept the nation this past summer. This was a major coup for research on ALS, also known as Lou Gehrig’s disease. By most accounts it resulted in more than $100 million going to several organizations that support ALS research. It also created a whole new level of awareness of the disease. I was very happy to see this. ALS is an awful disease and research to find treatments or a cure is highly worthy of support. It was also great to see the country so caught up in a movement for a good cause.A number of people have asked me if I wished the whole phenomenon had focused on Rett Syndrome instead of ALS. My answer—of course I do. How could I not? I have a daughter who struggles every moment of every day with Rett. What would I not do to hear her say “daddy” or “mommy” or to watch her walk across a room? It’s not just my daughter who moves me to say this; it’s also the more than 150 other girls and women with Rett Syndrome I’ve now met. It’s their faces and their expressive and intelligent eyes that keep me awake at night. So, yes, I wish the Ice Bucket Challenge had raised $100 million for Rett research to change their lives and my daughter’s life. That kind of funding would create a sea change for our research. It would greatly speed up progress. It would buy more time from the scientists who are already working so hard on Rett Syndrome; it would allow us to expand the number of researchers focusing on Rett; it would enable more projects and more scientific collaboration. In short, it would very likely have a tremendous impact on accelerating us towards what we all want so badly—effective treatments and a cure.
I could go on wishing, but that wouldn’t be very productive. So instead I started thinking about what I learned from the Ice Bucket Challenge and how I might apply it. I asked myself why people gave to this phenomenon so readily and generously. It’s clear that they weren’t giving because of information they got on ALS or the research. Most of the Ice Bucket videos I saw contained little or no information on ALS. So why did people give? I think they gave because of who asked them. They gave because they were “challenged” by someone they knew, trusted, and respected—a friend, a colleague, their daughter or son, their parents, or an old college or high school pal. Even celebrities gave because they were “challenged” by some other celebrity they know or work with.The Ice Bucket Challenge showed me that what’s all important is who is doing the asking. It showed me something that sounds basic, but is so important—that each of us has the power to ask and that we all can act on it with our own friends and family and make a difference to the research and to our daughters’, granddaughters’, sisters’, and nieces’ lives. And now, around the holiday season as the year is ending and people are thinking about their giving, is the best time to do it. I know I’m making it sound easier than it is. Asking people for money, even for a compelling and promising cause like ours, is hard. But what I find is that the results are surprising and rewarding—not just the fact that people give, but that they give so happily and that they are so pleased to be making a difference.
You might say to me—well that’s nice; but how do I ask? What do I say? Do I do it in person or in a letter or email? Those are all good questions. But there’s no one-size-fits-all answer. My advice is to tell your story about why you care about this, and then ask if people will give to this cause that matters so much to you. You know best what would work for your friends and family—maybe it’s a heartfelt letter or email; maybe it’s knocking on a few doors; maybe it’s taking a group of friends out for coffee or a drink. There’s no right or wrong way to do it. Keep it simple, be honest, respectful, and do it from the heart.
So this holiday season, if you’re not already involved with events or asking family and friends for support of the research, try it. Try asking a few people and see what kind of response you get. I think you’ll be pleasantly surprised. I am here to help if you want to think it through or run a letter by me. Please do not hesitate to call or email me any time. Thank you so much.
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.
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.