Is a Cure for Rett Really Around the Corner?

I’m a stickler for accuracy. I always have been. So I confess to being a tad uncomfortable when I see posts, videos, or comments saying, “A cure for Rett is right around the corner”.

It is my belief, that of our Chief Scientific Officer, Dr. Randy Carpenter, and our scientific advisors that a cure can only be delivered by addressing the root problem of the disorder, which is MECP2. While the drugs tested to date in Rett clinical trials may improve some of the symptoms, we do not expect them to deliver anything close to a cure.

So where do we stand with approaches that target MECP2? As a reminder these include gene therapy, RNA modifications, reactivation of MECP2, and protein replacement, which are the four approaches we have prioritized through RSRT’s strategic research plan, Roadmap to a Cure.

The closest to clinical trials is gene therapy. As most of you know, last year the biotechnology company AveXis announced that based on encouraging data generated by RSRT’s Gene Therapy Consortium they will be pursuing clinical trials. They are in the process of working with expert Rett physicians and Dr. Carpenter to design an initial clinical trial that optimally balances potential risks and benefits. Rest assured that AveXis is leveraging all insights gained from prior meetings with FDA to expedite progress with the Rett gene therapy program.

We are very upbeat about the potential of RNA modifications, which fix mutations at the RNA level rather than the gene level. This biological approach could also be a one-time treatment and will need to be delivered via a vector. So much of what has and will be learned in gene therapy will be relevant for RNA modification approaches. In addition to the progress by RSRT’s currently funded scientists, the last several months have seen exciting breakthroughs by other leading scientists in this rapidly advancing field. Our goal is to invest even more aggressively in approaches targeting RNA and to recruit additional world leaders to focus their research on Rett Syndrome. While this strategy is still novel with no clinical trials to date for any disease, our hope is that Rett Syndrome will pave the way forward.

In an attempt to reactivate MECP2 the scientists in our Reactivation Consortium have screened thousands of compounds. Several compounds were found to reactivate the gene to some degree but these compounds are unlikely to be safe enough to advance into clinical trials. Over the last year we have added biologic approaches to our reactivation arsenal. We recently awarded funding to the Jaenisch lab at the Whitehead Institute to work on a CRISPR approach and to the Philpot lab at the University of North Carolina to pursue a zinc finger approach. These biologic strategies will also require delivery via a vector, so once again, what we learn in gene therapy will have far reaching applications.

The final strategy that targets MECP2 is protein replacement. Delivering enough MeCP2 protein into the brain on an ongoing basis is currently difficult. Numerous scientists and biopharmaceutical companies are focused on improving delivery of proteins to the brain and we are poised to rapidly exploit new scientific breakthroughs.

With the exception of gene therapy, our other approaches are not yet ready for clinical trials. So how close we really are to a cure will depend, in large part, on the outcome of the AveXis gene therapy trial.

I suspect that the days and weeks after the first child gets dosed with gene therapy will be the most exciting and the most terrifying time in my life. Exciting because for the very first time the Rett community will have the opportunity to pursue an approach that attacks the root cause of this horrific disease. Terrifying because there are always risks to trying something for the first time and because although we expect dramatic improvements, there are no guarantees.

One thing I know for sure is that we would not be on the verge of gene therapy clinical trials if not for RSRT and our amazing families and their networks that support us. I’m very proud of that.

To everyone in our community who adores, like I do, someone with Rett, I make you three promises:

First, RSRT will not quit until we have a cure. Whether that cure “is around the corner”, meaning the upcoming gene therapy trial delivers the best possible outcome; or we determine that it is possible to modify and improve the gene therapy product; or if one of our other approaches takes the lead….we will not quit!

Second, RSRT will be bold in all of our activities, from fundraising to research. It’s the only way to make real progress.

Third, you will always get the truth from us. No spin. You deserve that.

So, is a cure around the corner? I honestly don’t know. But I can’t wait to find out.