COMPOSITIONS AND METHODS FOR TREATING OCULOPHARYNGEAL MUSCULAR DYSTROPHY (OPMD)

摘要

The present disclosure relates to modified adeno-associated virus (AAV) delivery vectors comprising 'silence and replace' DNA constructs, compositions comprising same, and the use of the modified AAV and compositions to treat oculopharyngeal muscular dystrophy (OPMD) in individuals suffering from OPMD or which are predisposed thereto. In particular, the disclosure relates to AAV having a capsid protein with a modified subunit 1 (VP1) and comprising a 'silence and replace' DNA construct, wherein the 'silence and replace' DNA construct comprises (i) a DNA-directed RNAi (ddRNAi) construct encoding short hairpin microRNA (shmiR) targeting PABPN1 causative of OPMD and (ii) a PABPN1 construct encoding functional PABPN1 protein having a mRNA transcript which is not targeted by the shmiRs at (i). The present disclosure also relates to the methods of treating OPMD comprising direct injection of an AAV of the disclosure to a subject's pharyngeal muscles.