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.

Image

by Diana Gitig

Clinical trials are designed to make sure that new therapeutics are both safe and effective. They can also be used to identify side effects, to compare how well different drugs work relative to each other and to see if certain populations react differently to different treatments. In order for doctors to prescribe the most appropriate drugs to their patients, they need to know the results of such clinical trials. Unfortunately, that information is not always so easy to come by.

Publication bias means that negative results generally do not get published. This is problematic because it skews the publication record. If only positive results get published, showing that a given drug is effective in assuaging a certain condition, people assume that that is the full story. Even if ten studies have been done showing that that same drug is useless, since negative data does not usually see the light of day no one knows about them and people think the published positive results are “fact.” Approximately half of all clinical trials performed globally have never been published in academic journals, and trials with positive results are twice as likely to be published as those with negative results. No one wants to publicize that their drug doesn’t work. Because if doctors don’t know that a drug doesn’t work – or a more realistic scenario, that a new, expensive drug doesn’t work better than the old generic – then why on earth wouldn’t they prescribe that drug to their patients? Moreover, it has been perfectly legal for pharmaceutical companies and universities to withhold the results of clinical trials as proprietary information.

To mitigate the misperceptions caused by publication bias and the withholding of trial data by the pharma industry, the Food and Drug Administration Modernization Act of 1997 created ClinicalTrials.gov. All clinical trials with at least one testing site in the US are supposed to register there before the trial starts. It went online in 2000 but only really became a force in 2005, when the International Committee of Medical Journal Editors made registration a prerequisite to having a trial published in a journal. Since researchers must register before the trial begins, they must lay out their initial hypothesis and thus cannot “move their goalposts” – claim to have always been looking for whatever it was they found. In 2007, the FDA added the requirement that results must be published on the site within a year after a trial is completed. Thus even if results are not published in journals doctors and patients have another place to search for them, and it should, in theory, be more difficult for researchers to hide negative results, since there is a record of the trial having taken place.  However, neither the requirement to register trials nor the requirement to report results have been rigorously enforced or followed. So often not only do doctors still not know the results of trials – they might not even know that a trial has been done.

On April 2, 2014, the Members of the European Parliament voted to adopt the Clinical Trials Regulation. This regulation makes it law in the European Union that clinical trials be registered before they begin, that results be published somewhere within a year after the trial ends, and that a summary of results written in lay terms be published on the publicly accessible register. Failure to comply with these new requirements will be punishable by a fine. It also dictates that information contained in Clinical Study Reports will no longer be considered commercially confidential. These reports contain many details that are often omitted in academic papers but are nonetheless important, like research methodologies.

This new European law is expected to come into effect in mid-2016 at the earliest. It is an enormous stride forward, but most of the medicines currently in use went through trials that have already been done. Results of these trials can still legally be withheld, so doctors must still make prescribing decisions without complete, accurate, and up-to-date information about which drugs now available are best for which patients.

Those with rare diseases can be particularly impacted by the transparency, or lack of it, in clinical trials. Pooling results from different studies into meta-analyses can often reveal the most telling effects of a drug; since fewer people have these disorders fewer studies can be done, and thus withholding data from any one of them can thus have an outsize effect. Moreover, subjects who participate in such trials often do so to benefit their fellow patients in addition to themselves, and withholding the results that they helped provide is a betrayal of their trust.

http://www.alltrials.net/

http://www.badscience.net/

http://www.thepharmaletter.com/article/meps-vote-for-more-transparent-and-simpler-european-clinical-trial-rules

http://www.bmj.com/content/348/bmj.g213?ijkey=5aXoYcMGOETixKf&keytype=ref

http://www.nimh.nih.gov/funding/opportunities-announcements/clinical-trials-foas/changing-nimh-clinical-trials-efficiency-transparency-and-reporting.shtml

http://www.nimh.nih.gov/about/director/2014/a-new-approach-to-clinical-trials.shtml

 

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

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The Milken Institute Global Conference, which explores solutions to pressing challenges including healthcare, took place today in Los Angeles.  FasterCures reported on the conference proceedings with the blog post below – two facts caught our attention:

  • Only 1 of every 10,000 academic discoveries make their way into the hands of patients….
  • Industry has 0.1% of scientists in world.  They are as good as any other scientists, but they’ll only have 0.1% of ideas. 

These facts truly bring home the message that academia and industry must work together.  And advocacy groups such as RSRT can play a major role in catalyzing these interactions.

FasterCures Blog

“We don’t just want to chase cures, we want to catch them,” said National Institutes of Health (NIH) Director Francis Collins at the Milken Institute Global Conference today in Los Angeles.  His comment aptly captured the prevailing sentiment of a panel of life science experts who came together to discuss creative strategies for speeding and improving medical progress across diseases in the face of limited resources. 

As moderator Melissa Stevens (Deputy Executive Director, FasterCures) pointed out, our knowledge of disease has never been deeper, but our need for cures has also never been greater.  Only 1 of every 10,000 academic discoveries make their way into the hands of patients, and the cost of developing a new therapy can soar as high as $1 billion. But it’s not all bad news.  With greater cross-sector collaboration and increasing levels of openness in research, we are poised to capitalize on the scientific opportunities before us.  “But we have to stop playing like solo artists, and start playing like a band,” said Stevens.

When asked how that band could best jam together, Collins gave the example of NIH’s Accelerating Medicines Partnership. A new venture between the NIH, 10 biopharmaceutical companies – including Johnson & Johnson and GlaxoSmithKline, both represented on the panel – and several non-profit organizations, it seeks to transform the current model for developing new diagnostics and treatments by jointly identifying and validating promising biological targets of disease.

Melinda Richter, Head of Janssen Labs, talked about industry’s commitment to sustaining innovation through collaboration, citing Johnson & Johnson’s role as key architect of Transcelerate and creator of the YODA project, as examples. “Jannsen labs enables scientists to think about their science in a commercial way, and creates a financial marketplace where people with money looking for technology and people with technology looking for money can find each other.” She went on to note that industry has a duty to make sure there is a strong investment profile for individuals looking to put money into the field. 

“There is a new level of humility within industry,” said Moncef Slaoui, Chairman, Global R&D and Vaccines at GlaxoSmithKline, who noted that the private sector recognizes the need to embrace open innovation and collaboration to solve medical challenges. “Industry has 0.1% of scientists in world.  They are as good as any other scientists, but they’ll only have 0.1% of ideas.  The other ideas are happening elsewhere so we need to figure out where and how to combine forces.”

Continue reading

by Diana Gitig

Science, Nature, and Cell, The New England Journal of Medicine, The Lancet – these most prestigious of scientific and medical journals are published on a weekly basis, each week’s issue brimming with amazing new discoveries claiming to expand the state of knowledge in their respective fields, or better yet, to shatter current paradigms and shift future research to a new direction. Yet not every published paper stands the test of time; few manage to actually shatter paradigms, and there are those whose results even fail to be replicated by other scientists. The process of peer review is the method most journals use to vet their papers, to try to ensure that the results they publish are correct more often than not.

It works like this: after years of toil by graduate students and postdocs, a lab head prepares a manuscript describing their hypothesis, the experimental methods they used to test the hypothesis, the results of those experiments, and their interpretations of those results. Sometimes results prove the hypothesis to be true, and sometimes to be false. Either way, the results often suggest avenues for future research. Then the researchers must choose a journal, and send their manuscript off to the editors.

If the paper is obviously terrible or fraudulent, the editors will reject it outright. And if it is obviously earth shattering – and has well-controlled experiments, and an argument that flows logically from the results – they will accept it immediately without reservation. Since in the real world neither of these things ever actually happens, editors usually send the paper out for peer review, asking two to four scientists familiar with the field their opinions of the paper.

These peer reviewers must assess if the experiments used were the most appropriate ones available to test the hypothesis in question; if the experiments were performed properly; if the authors’ conclusions are consistent with the results obtained; and if the findings are significant – i.e. new and sexy – enough to warrant publication. Often, the reviewers will suggest that the authors modify wording, or  perform additional experiments, before the paper is published. This back and forth can take up to a year. These reviewers are anonymous, so the authors don’t get to engage with them directly. And the reviewers don’t ultimately decide if the paper gets published; the editors of the journal make that decision, based on the reviewers’ recommendations. If the paper is rejected, the authors are free to try the whole process again at a different journal.

Like most things in this world, peer review is not perfect. Reviewers must obviously be familiar with the topic at hand, so they are often colleagues – and can be competitors – of the researcher whose work they are reviewing. They can hold up the publication, or utilize the ‘insider information’ they glean from the paper to advance their own research. But on a less nefarious level, they are busy scientists who are not being compensated for their time reviewing this new paper, so it is often not their top priority. Nor have they had any training as to how to review a paper, since it is not built into science education. They also never get an assessment of their reviews, so they don’t know if they were helpful or if they need to improve. And peer review is not designed to pick up fraud or plagiarism, so unless those are really egregious it usually doesn’t.

Funding requests, like those submitted to RSRT, are subject to a very similar system. Just like journal editors, the people handing out research money rely on expert opinions to decide who gets how much. A grant is slightly trickier than a paper submitted for publication, though, because nobody knows a priori if the proposed experimental methods will work as hoped, or how significant the results might be.  As mentioned above, these things are difficult enough for reviewers to assess once the results are in – and in a grant application, the experiments haven’t even been done yet.

To minimize this risk RSRT employs a fastidious peer review. Reviewers are selected with painstaking attention to fields of expertise and potential conflicts of interest including philosophical or personality conflicts. Proposals are judged for relevancy to RSRT’s mission, scientific merits of proposed experiments and strength of the investigator.

There are stirrings of change to deal with these problems. Many scientists think that established journals have a chokehold on research by deciding what gets published, and are playing with a more open system whereby scientists publish their findings online – often for free, in contrast to traditional journals which charge a hefty fee for publishing a paper – where they are then subject to a more transparent post-publication peer review. Some examples are PLoSOne, BioMedCentral, and F1000Research. Other researchers think pre-publication reviews should be signed, so the reviewer has some accountability.

Forums that allow for ongoing critiquing of papers after publication are gaining momentum.  Examples include PubMed Commons, PubPeer, Open Review. RSRT is a fan of post publication peer review and has long employed this approach to evaluate papers in the Rett field.

One way scientists assess the relative importance of an academic journal is by its impact factor, a way to measure a journal’s prestige. It measures the average number of times recent articles published in the journal have been cited in a given time period, usually a year. Journals with higher impact factors – like those that began this piece – are deemed more important than those with lower ones. Impact factors have been published annually since 1975 for journals that are indexed in Journal Citation Reports and have been tracked by Thomson Reuters (ISI) for three years.

No scientific paper is intended as the be all and end all of truth. That is how the scientific method works, and where its beauty lies; each discovery is “true” only until new experimental evidence comes along that refutes it. Peer review cannot guarantee that a paper’s results will be reinforced over time. But it does act as a gatekeeper or first responder, trying to ensure that papers that are published in scientific journals are experimentally and logically sound.

References/ Further reading

http://arstechnica.com/science/2010/11/the-vagaries-of-peer-review/

http://boingboing.net/2011/04/22/meet-science-what-is.html

http://www.wired.com/wiredscience/2012/02/is-the-open-science-revolution-for-real/

http://blogs.scientificamerican.com/the-curious-wavefunction/2013/01/29/peer-review-pitfalls-possibilities-perils-promises-scio13/

http://johnhawks.net/weblog/topics/metascience/journals/tracz-interview-f100research-2013.html

http://wokinfo.com/essays/impact-factor/

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]

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.

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