TH.O.15 - Gene therapy for oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset autosomal dominant muscular dystrophy affecting 1:100000 people in Europe. OPMD is due to mutation in polyA binding protein nuclear 1 (PABPN1) gene that presents an abnormal expansion of alanine-encoding GCG trinucleotide repeats. Due to this mutation, patients express a protein with 11–17 alanines (expanded PABPN1, expPABPN1) instead of the normal 10 that is misfolded and prone to form intranuclear inclusions (INIs). OPMD is mainly characterized by progressive eyelids drooping (ptosis) and dysphagia although also muscles of the lower limbs can be affected late in life. Currently no pharmacological treatments are available and OPMD patients can only be referred to surgeons for cricopharyngeal myotomy or corrective surgery to extraocular muscles to ease ptosis. Inhibiting the expression of expPABPN1 is an appealing strategy but such approach would invariably affect the expression of wild type PABPN1 with negative effects on treated muscles. Here we describe an AAV-based “silence and replace” strategy in a mouse model of OPMD where combination of complete knockdown of the endogenous PABPN1 and its replacement with a sequence optimized, wildtype PABPN1 significantly reduced the amount of INIs, decreased fibrosis, counteracted muscle atrophy, restored muscle strength and normalized the muscle transcriptome. These results support the application of a gene therapy approach as a novel treatment for OPMD in humans.