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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.


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


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

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.

To profoundly impact a disorder with as many varied and debilitating symptoms as Rett Syndrome, it is likely that intervention must be directed toward the very root of the problem. There are several ways to do this: activate the silent back-up copy of the Rett gene; target modifier genes; explore gene therapy.

Today, we announce a study funded through the MECP2 Consortium suggesting that gene therapy may indeed provide a feasible approach to treat Rett Syndrome.

The work was led by Gail Mandel at Oregon Health and Sciences University in collaboration with Adrian Bird of the University of Edinburgh and Brian Kaspar of Nationwide Children’s Hospital.

Gail Mandel with lab members Dan Lioy and Saurabh Garg

Gail Mandel with lab members
Dan Lioy and Saurabh Garg

Adrian Bird and post-doc Hélène Cheval

Adrian Bird and post-doc
Hélène Cheval

In the past sixty days, four key papers have been published detailing research advances supported financially and intellectually by RSRT. Three of those papers are funded through the MECP2 Consortium, a unique alliance launched by RSRT in 2011 among three leading labs: Bird, Greenberg (Harvard) and Mandel. If you are a donor to RSRT, the accelerated research these projects represent is the result of your money at work.

We wish to express our gratitude to all of our generous supporters and the parent organizations that make this progress possible. Special thanks to our funding partners, the Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation.

Below are some resources to help you understand today’s announcement.

Press Release [Spanish Translation] [German Translation]

Video interview with Dr. Mandel & lab members