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.
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.
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.
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.