Funding outcome

Facioscapulohumeral muscular dystrophy (FSHD} is a genetic disorder characterized by the progressive weakening and wasting of muscle in the face, shoulders, and limbs. The disorder usually first manifests in the upper body, after which it descends to the lower regions with age. FSHD is the third most common form of muscular dystrophy. While the disorder has a variable age of onset, most patients begin to show symptoms during the teenage phase of childhood. There is also an infantile form of FSHD, starting as early as 10 years of age, which is notably associated with more severe symptoms. Once the disease has started, patients are subject to a lifetime of disability. There is currently no cure for FSHD. My proposed research aims to develop a new treatment for FSHD. FSHD is caused by the abnormal production of a protein called DUX4 in muscle cells. Healthy muscle cells do not have DUX4. I plan on using small DNA-like molecules called gapmers to decrease the amount of DUX4 protein in muscle cells. Gapmers are able to do this by specifically finding and destroying the gene products responsible for making DUX4. Preliminary data obtained by our research group has already shown that gapmers designed to be specific for DUX4 are capable of decreasing DUX4 protein amounts in muscle cells from FSHD patients. In this proposed project, I will be further assessing the efficacy and safety of a number of these DUX4-specific gapmers using FSHD patient-derived muscle cells. Different gapmer doses will be tested, and corresponding effects on treatment effectiveness (i.e., DUX4 reduction} and safety will be comprehensively evaluated using a wide array of molecular and cell-based tools. Once the best gapmer for treatment has been determined, further studies will be done in an FSHD mouse model with the help of a collaborator. This study will ultimately result in the identification of a clinical trial drug candidate for FSHD treatment. As mentioned, FSHD usually begins in childhood and has an aggressive form that particularly affects children. Therefore this study will provide significant positive impact to the lives of children affected with FSHD so that they, together with other FSHD patients, are provided with an opportunity to live without the constraints of disability and have an improved quality of life.