Optimizing Gapmer Therapy for Facioscapulohumeral Muscular Dystrophy

Budget

• Amount awarded: US$125,969
• FSHD Canada Foundation Contribution: US$25,000 (jointly with the FSH Society)

Timeline

• One Year

Lay Abstract

Principle Investigator: Yi-Wen Chen

Research Institution: George Washington School of Medicine

Antisense oligonucleotide (AON) therapy is a promising approach to treating FSHD. However, several issues arise with AONs including: difficulty in delivering the drug into the muscles; harmful side effects and toxicities; rapid degradation in the body so that the AON can’t provide its beneficial function; and immune responses induced by the AONs. To address these issues, one can chemically manipulate the AON. One method uses 2’-O-methoxyethyl (2’MOE), and the other is called locked nucleic acids (LNAs). The 2’MOE chemistry was used in the FDA-approved treatment for spinal muscular atrophy.

In a previous study supported by the FSH Society, Chen and her collaborator Toshifumi Yokota, PhD, at the University of Alberta, showed that an “LNA gapmer” was effective in knocking down DUX4 in cell culture and improved muscle strength in an FSHD mouse model. In this proposal, the Chen lab will test 2’MOE gapmers targeting DUX4. This construct may be less potent but safer than the LNA gapmer. Yokota has shown that the 2’MOE gapmers effectively knocked down DUX4 transcripts in the test tube. Chen will compare the efficacy and safety of the 2’MOE gapmers in mice. The goal is to carefully characterize and identify the most promising candidate to develop as a therapy.