Summary of paper in Molecular Therapy from Joel R. Chamberlain and Davide Gabellini

by Joel Chamberlain


Joel R Chamberlain
Joel R Chamberlain

Bortolanza, SB, Nonis, A, Sanvito, F, Maciotta, S, Sitia, G, Wei, J, Torrente, I, Di Serio, C, *Chamberlain, JR, and *Gabellini, D: AAV6-mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy. Molecular Therapy (2011) Aug 9; doi:10.1038/mt.2011.153.

I am pleased to report the publication of our study focused on developing a treatment for FSHD using a broadly applicable approach to eliminate proteins that cause the disease. We were able to effectively harness a naturally occurring cellular process for regulating gene activity, referred to as RNA interference (RNAi), as a basis for the therapy in a model of FSHD. The study took several years to complete in Seattle and Milan, Italy, involving an extensive collaborative effort with Dr. Davide Gabellini, his postdoctoral fellow Dr. Sergia Bortolanza, and other colleagues.

Discovery of the RNAi mechanism for fine-tuning gene regulation in the cell in the 1990s received much attention and a nobel prize was awarded to recognize this scientific milestone. Since that time researchers focused on understanding the cellular machinery involved in the RNAi pathway and potential ways to co-opt the process for therapeutic applications. My laboratory decided to combine our method of delivering genes to muscle with a way to activate RNAi to prevent the cell from making proteins necessary for developing FSHD. In essence, we use the "shell" of a muscle-loving virus that does not cause disease in humans, and replace the contents of the virus with instructions on how to specifically eliminate the unwanted protein involved in disease. We tested our method in mice with a muscular dystrophy similar to FSHD (FRG1 model) and found that we could undo damage already beginning in muscle and prevent long-term weakness in the mouse that would occur without treatment. Mice were treated as adults, after onset of disease, and were monitored for their ability to run in weekly trials over an 11-week period after treatment. We observed progressive strengthening of muscles as the treated mice improved in their ability to keep up with normal mice in a running study. A similar approach was used by Dr. Scott Harper (Columbus, OH), also published recently in Molecular Therapy, to show prevention of muscle damage before onset of disease in the FRG1 model and our complimentary studies support the feasibility of this method.

The findings of our research are significant in 2 important ways for FSHD therapy development. First, we have shown that our RNAi approach is safe and potent enough to reverse and halt progressive disease. Second, our method lends itself to adaptation for preventing expression of other unwanted cellular proteins involved in FSHD, such as DUX4, and we have made these versions of our therapy and are testing them now. Of more broad application to the muscular dystrophy field, our approach can be applied to any muscle disease like FSHD where we need to eliminate a disease-causing cell product.

We are cautiously optimistic about prospects for developing this approach into a treatment for FSHD. Our next step is to apply our approach to eliminating DUX4 in FSHD models of disease as the most promising target for therapy. In addition, several issues must be addressed before routine clinical application of the RNAi approach is possible. These issues include safety and effectiveness regarding immune responses of the body to the therapeutic virus delivery system and also safety and effectiveness of the therapeutic RNAi component that can cause interference with the normal function of the RNAi pathway in cells. Clinical trials are progressing our understanding of the virus shuttle, but the shuttle is not yet ready for routine use. Some progress in using this type of RNAi therapeutic appears safe in limited studies, although widespread delivery in muscle has not been tested in patients.

Dr. Joel R. Chamberlain began her career in the FSHD field with funding from Friends of FSH Research, and has received additional support from the Muscular Dystrophy Association to continue this work.