We’ve known for almost two decades that mutations in the MECP2 gene and its corresponding protein, MeCP2, cause Rett Syndrome. During this time a variety of biological functions have been attributed to the MeCP2 protein, but with no clear evidence for how these various functions relate to Rett Syndrome.
Years of research, much of it funded by RSRT, defining the biologic effects of the most common mutations are now beginning to provide new insights. Adrian Bird and his colleagues proposed a simpler view in 2013 when publishing data indicating that MeCP2’s key role is to bridge DNA with a repressor complex called NCoR. They theorized therefore that the parts of the MeCP2 protein that bind to DNA and to NCoR are the most important “real estate” on the protein. These domains are called the MBD (methyl DNA-binding domain) and NID (NCoR interaction domain).
Adrian Bird, who is part of our MECP2 Consortium, in collaboration with Stuart Cobb, a member of our Gene Therapy Consortium, now have strong evidence in support of this “bridge theory”. Their research, funded in part by RSRT, is being published online today in the journal, Nature.
The Bird lab hypothesized that if the primary function of MECP2 is to form a bridge between DNA and NCoR then perhaps the other parts of the gene aren’t vital. They took the MECP2 gene and chopped off everything before the MBD and after the NID to create a shortened gene.
Then they created a mouse model with this shortened gene instead of the full length MECP2 gene. The mice turned out to be remarkably normal. The scientists then went a step further and additionally removed the bit between the MBD and NID.
They created yet another mouse model with this mini-gene and these mice lived almost as long as normal mice and although they did have some symptoms, these were extremely mild.
The scientists then recreated the Bird reversal experiment of 2007, but this time the mice were designed so that the mini-gene rather than the full-length gene could be switched back on. When the mini-gene was switched on and started to make its mini-protein the Rett-like symptoms were relieved.
In the final experiment the scientists used gene therapy to deliver the mini-gene. Newborn Rett mice that received the mini-gene via gene therapy developed much milder symptoms and lived dramatically longer lives. Experiments currently in the works are aimed at further improving efficacy and testing the gene therapy in symptomatic mice, both male and female. Although the mini-gene may not correct all manifestations of Rett Syndrome, the smaller size provides theoretical advantages for delivery of the mini-gene or mini-protein to humans.
In June, we announced that the biotech company, AveXis, will be pursuing clinical trials of a first generation full-length gene therapy product. This is an exciting development with potential to provide profound therapeutic benefit. We are optimistic that significant efficacy will be observed, but it’s also very important that we continue to pursue alternative curative approaches. RSRT’s goal is to have a rich pipeline of therapeutics that offer our children the best chances of recovery. This is why through our Roadmap to a Cure we are supporting the parallel development of second-generation gene therapy products, like the mini-gene, as well as RNA approaches, MECP2 Reactivation and protein replacement.
We thank all our generous supporters whose vision and commitment makes our work possible. And congratulations to the Bird and Cobb labs on their important publication.
For more coverage on this, head over to Spectrum.