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.

consortium

From left moving clockwise:
Sarah Sinnet (Gray lab), Steve Gray, Brian Kaspar, Stuart Cobb, Saurabh Garg (Mandel lab), Kamal Gadalla (Cobb lab). 
Guest participant Ruth Shah (Bird lab) joined the meeting by Skype as did Gail Mandel and Mark Bailey.

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-03Consortium 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

gail

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

kasparThe 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

cobbThe 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

grayOur 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

Dear Friends,

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.

photo[7]

Eleanor, Tim’s daughter, receiving her first haircut

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.

photo[8]

Tim with Jocelyn Jones

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.

photo[7]

Andrea and Charlotte Bryman with Tim

 

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.

Tim Freeman

by Monica Coenraads

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

Chelsea beach

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

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

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

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

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

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

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

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

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

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

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

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


Rousing silenced X chromosome may treat Rett syndrome

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

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

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

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

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

Continue reading

Frank Menniti Chief Scientific Officer  Mnemosyne Pharmaceuticals

Frank Menniti
Chief Scientific Officer
Mnemosyne Pharmaceuticals

Discovering drugs to treat diseases of the central nervous system is a formidable task.  Our brains are easily the most complex machines on the planet and the more we learn about this machine, the more daunting seems the task of fixing it when things go wrong.  This point is brought home for me when meeting people with some of the CNS disorders I hope to help treat.  I’m new to Rett Syndrome but have now been to a couple of events along with girls suffering Rett and their families.  How can a mutation in a single gene result in such a complex outcome?!  There is a specific answer to this question, because MeCP2 mutation causes Rett, a specific disease.  Yet it is a long and winding road from MeCP2 to that characteristic hand wringing and the many other symptoms Rett girls experience over a lifetime.  Where to step in with a drug therapy and what to expect as an outcome?

The best way to deal with such complex drug discovery problems is head on – identify the root cause of a disorder, fix that, and relief from even the most complex symptoms should follow.  For Rett, there is very good basic science data to suggest that if we restore MeCP2 function then we will restore brain function, and so with habilitation therapy achieve a cure.  Encouraging research along this line is ongoing and we can hope for success.

However, many, if not most, of the drug discovery efforts around Rett syndrome target the consequences of MeCP2 mutations to provide a therapeutic benefit. Put another way, these approaches aim to mend the damage done to the brain that results from lack of functional MeCP2.  In fact, this is the most common approach in CNS drug discovery, where root causes are seldom clear.  Such approaches can be quite effective. Perhaps the best example is in Parkinson’s disease, where dopamine neurons in the brain die off.  We don’t know why dopamine neurons die or how to prevent this die off, that is, how to fix the root cause of Parkinson’s. But we have a pretty good understanding of the dopamine system and from this knowledge drug therapies, and more recently deep brain stimulation therapies, have been developed that compensate for the loss of dopamine neurons.  Take a look at this YouTube video of the effect of deep brain stimulation in a Parkinson’s patient.  Clearly, this patient is being enormously helped by his therapy, even though the therapy does not fix the root cause of dopamine neuron loss.

Can we fix the Rett brain and anticipate that complex symptom relief will follow? I think the answer is ‘yes’.  And, there is a guidepost on how we may go about this in the efforts being made to discover new therapies to treat cognitive defects in schizophrenia.  Schizophrenia, like Rett, is a neurodevelopmental disorder that results in an incredibly complex and variable array of symptoms.  Of these, the cognitive deficits are the most debilitating, keeping patients out of school and work even after their more florid symptoms are under control.  But these cognitive deficits are complex, as are their outcomes (that’s an understatement!).  How would we know that a new therapy had a meaningful effect in the face of such complexity, let alone how to prove a benefit in a Phase II clinical trial?  The schizophrenia research community, NIMH, FDA, and the pharmaceutical industry, took this problem on and the result was the MATRICS and CNTRICS Initiatives.  In MATRICS, complex global cognitive deficits in schizophrenia were broken down into simpler components like working memory, for example as measured in the ability to remember a short word list.  The idea is that improving a patient’s working memory, coupled with habilitation therapy, would make the patients better able to keep track of tasks and so hold a job or finish school.  CNTRICS takes this one reductionist strategy one step further by trying to identify the fundamental physiological brain abnormalities that underlie the simpler cognitive components.  For example, associating an EEG abnormality with a working memory deficit.  The logic now is that, if we fix the EEG abnormality, we will fix working memory, and the patient has an improved cognitive toolbox to use in daily life.  Clinical trial follows this progression – first, fix the EEG abnormality, which is most quantifiable and requires the smallest number of patients; second, take the learnings on drug dosing etc. from the EEG trial to prove a reliable drug regimen that fixes working memory; third, use this drug regimen, in combination with habilitation, to explore the potential for ‘real life’ benefits.

I think a structured approach following a MATRICS/CNTRICS model could be very impactful in developing drug therapies for Rett. But the devil is in the details.  The most obvious and immediate questions are scientific- what to measure first, second, third?  Less obvious but no less important are questions around clinical development strategies and timelines for such an approach.  Where along such a path does such a drug become approved and so commercially available?  These latter issues will require significant thought and discussion among all in the Rett community.  More of my thoughts on the science and these broader issues in future posts.

 

by Monica Coenraads

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

1623703_516732648427830_2098385048107441333_n

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

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

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

y-chromosome

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

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

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

Dear Friends,

Tim and his daughter Eleanor

Tim and his daughter Eleanor

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

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

MacDonald Family at this year’s Quest for a Cure

Tim and MacDonald family at the
Quest for a Cure event

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

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

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

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

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

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

I look forward to hearing from you. Thank you.

Tim Freeman

 

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

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

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

by Monica Coenraads

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

healthy-mutant

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

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

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

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

Bryan Roth

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

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

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

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

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

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

 

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

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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

 

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