PABPN1 gene therapy for oculopharyngeal muscular dystrophy

Nat Commun. 2017 Mar 31:8:14848. doi: 10.1038/ncomms14848.

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gene Knockdown Techniques / methods
  • Genetic Therapy / methods*
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Transgenic
  • Muscle Strength / genetics*
  • Muscular Dystrophy, Oculopharyngeal / physiopathology
  • Muscular Dystrophy, Oculopharyngeal / therapy*
  • Myoblasts, Skeletal / metabolism*
  • Poly(A)-Binding Protein I / genetics*
  • Transcriptome / genetics*
  • Trinucleotide Repeat Expansion

Substances

  • Poly(A)-Binding Protein I