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Gene Therapy Consortium

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.

But how do we make the giant leap from recovered mice to recovered children and adults?

To move us towards this goal as rapidly as possible, RSRT launched the Gene Therapy Consortium, a bold international collaboration among four laboratories who together bring all the necessary skills to determine if gene therapy is a feasible approach. 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.

Meet the Consortium Members

The Consortium is comprised of two gene therapy labs, Brian Kaspar and Steven Gray, and two labs with expertise in the Rett gene and mouse models, Gail Mandel and Stuart Cobb. In late 2016 we renewed funding and welcomed Alysson Muotri to the Consortium.


Steven Gray is at University of North Carolina, Chapel Hill, where he has successfully navigated a gene therapy program from the bench into human clinical trials.


Brian Kaspar is at Nationwide Children’s Hospital where he has successfully navigated two programs from bench research to human clinical trials.


Stuart Cobb is at the University of Glasgow and was one of the authors of the reversal paper published in 2007. 


Gail Mandel, from OHSU, has been involved in Rett Syndrome research for over a decade and has made seminal discoveries.


Alysson Muotri has been working on Rett Syndrome for over a decade, first in the laboratory of his mentor, Fred (Rusty) Gage at the Salk Institute, and now at UCSD.

Why Gene Therapy?

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, it’s conceivable that gene therapy can correct the cause of Rett at its source and thus provide a profound recovery of function.

There are several major advantages that Rett offers:

  1. The genetic target is known: MeCP2
  2. Rett is not neurodegenerative – neurons don’t die
  3. We know that restoring the proper level of MeCP2, even later in life, at least in a mouse, results in dramatic improvements.

Why Now?

Following several decades of rocky ups and downs, the gene therapy field is coming into its own due to major advances in molecular biology and viral technologies. Europe and Asia recently approved several gene therapy products. Worldwide there are hundreds of clinical trials ongoing. Industry is investing enthusiastically in this area resulting in numerous gene therapy biotech startups.

Our Consortium members are gaining valuable experiences with their own trials. Dr. Kaspar has been instrumental in the launch of a trial for Spinal Muscular Atrophy (SMA) that was the first to use an AAV vector. Reported results indicate that the AAV vector has been safe and well tolerated. Most importantly, the gene therapy has produced profound, and unprecedented, efficacy in children with SMA. RSRT’s lead gene therapy program is using the same AAV vector, and has demonstrated excellent safety and efficacy in animal models. Dr. Kaspar is also involved in a Batten Disease trial. 

Dr. Grey has played a major role in the launch of a trial for Giant Axonal Neuropathy that administers an AAV vector into the spinal fluid. His lab focuses on gene therapy platforms for neurological diseases. He has made enormous strides using existing vectors (the Trojan horses that deliver genes into cells) to their full potential, and also leading the way to develop newer and better vectors.

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.

StePHEN Gray

University of North Carolina Chapel Hill

What have we learned thus far about Gene Therapy for Rett?

Multiple labs have shown that a single one-time administration of a gene therapeutic can have a clinically meaningful result in the mouse model of Rett syndrome, even when delivered after symptoms have developed. Consortium members have collaborated to identify critical factors that improve both efficacy and safety.

We have also learned that a substantial therapeutic impact may be achieved by delivering the gene to a subset of cells. This is very encouraging as it is currently not possible to deliver the gene to every cell in the brain.

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.

What are the challenges?

There are several hurdles to overcome. There is a requirement for MECP2 in every part of the human brain so the gene will need to be broadly delivered. Higher doses should improve delivery, but we know that too much MECP2 can cause serious symptoms. Thus, dose selection will be important. It is encouraging that female mice appear to tolerate higher levels of MECP2, especially delivered later in life. However, safety and efficacy of gene therapy will ultimately need to be defined in humans.

We believe the efficacy, safety and delivery characteristics of our lead gene therapy construct supports advancement into human clinical trials.

It is very stimulating to be part of such a focused group of experts on gene therapy approaches towards Rett. 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.


Oregon Health & Science University

What We’re Working On

  • Vector Optimization – The vector is the Trojan horse that delivers the working copy of the gene into a cell. Novel vectors are being developed at a rapid pace. Consortium members will focus on the new vectors that offer potential advantages over the current vector. The goal of this effort is to achieve better distribution to all brain cells.
  • Optimizing the Gene Construct – The rapid pace of advances in the scientific understanding of Rett Syndrome and gene therapy provides numerous opportunities to incorporate novel insights into the design of the gene and regulatory elements. The goal of this effort is to improve the regulation of MeCP2 protein production in the brain cells.
  • Optimizing how much Gene Therapy to Deliver –  The scientists will assess the interaction of vector and gene construct on dosages required for efficacy versus toxicity. The goal being to increase the “therapeutic window” between doses producing beneficial effects and those producing adverse effects.
  • Delivery Route Optimization  – Gene therapy can be delivered via the blood stream, directly into the brain, or into the spinal fluid that bathes the brain. Each route has its own advantages and disadvantages and each route has been used in clinical trials for other disorders. The goal is to identify the optimal route of delivery for each new vector and gene construct.

Spliceosome-Mediated RNA Trans-Splicing Therapy in Rett Syndrome

Targeting MECP2 can be done either at the DNA, mRNA or protein level. Both the DNA and protein approaches have a complication due to potential dosage problems (too much MeCP2 may be harmful).

An alternative approach is to use a technology called Spliceosome-Mediated RNA Trans-Splicing (SMaRT). This technology allows a mutation to be spliced out and repaired in RNA. The advantage is that this approach avoids any potential over-expression issues.

The possibility of correcting mutations at the level of RNA has profound therapeutic potential, but had remained largely theoretical. Focused investments by RSRT have already demonstrated the potential for correcting MECP2 mutations at the level of RNA in cells. We are currently increasing our investment to aggressively pursue this therapeutic approach.

Goals during the next three years are to improve the efficiency of editing RNA in the brain and to identify optimal delivery methods.

Current Projects