500. Gene Therapy Rescues Disease Phenotype in the Oculopharyngeal Muscular Dystrophy Mouse Model

Among triplet expansion diseases, oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. OPMD is caused by a short trinucleotide repeat expansion in the polyadenylate-binding protein nuclear 1 (PABPN1) gene that results in an N-terminal expanded polyalanine tract. PABPN1 controls several biological processes such as the length of mRNA poly(A) tails, the mRNA export from the nucleus and the alternative poly(A) site usage. OPMD is characterized by nuclear aggregates of expanded PABPN1, fibrosis and muscle atrophy. Here we demonstrate that treating mice affected by OPMD over 4 months with an AAV gene therapy strategy based on DNA-directed RNA interference to silence the endogenous expPABPN1, combined with the re-expression of a healthy sequence-optimized human PABPN1 gene, significantly reduced the amount of nuclear aggregates in affected muscles, decreased the intramuscular fibrosis and reverted the muscle strength to the level of healthy wild-type muscles. Furthermore, although muscle atrophy was not reverted, the expression of a healthy PABPN1 markedly increased the cross sectional area of muscle fibres. These results obtained in a relevant mammalian animal model of OPMD pave the way for the clinical application of a gene therapy approach as a treatment for OPMD patients.