PABPN1 gene therapy for oculopharyngeal muscular dystrophy

A Malerba,P Klein,M Polay Espinoza,G Cordova,C Trollet,V Mouly,S A Jarmin,H Bachtarzi,G Dickson,K Mamchaoui,S C Blumen,J Lacau St Guily,M Graham,D A Suhy,V Strings,G Butler-Browne,A Ferry

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.

Highlights

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
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, degenerative muscle disease affecting about 1/100,000 people in Europe that usually presents in the fifth decade of life[1]
Individuals affected by OPMD have a mutation in the PABPN1 gene, coding for polyA-binding protein nuclear 1 (PABPN1)[3], an ubiquitously expressed polyadenylation factor involved in many biological processes[4]

Summary

Introduction

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. Individuals affected by OPMD have a mutation in the PABPN1 gene, coding for polyA-binding protein nuclear 1 (PABPN1)[3], an ubiquitously expressed polyadenylation factor involved in many biological processes[4]. Other pharmacological strategies currently under pre-clinical investigation include antiprion drugs like 6-aminophenanthridine and guanabenz, and targeting the expPABPN1 with intracellular antibodies[25,26,27]. None of these strategies directly correct the genetic defect of OPMD patients. A recent phase I/IIa clinical trial that employed transplantation of unaffected autologous myoblasts in combination with the cricopharyngeal myotomy ameliorated the pathology of OPMD patients with a cell dose-dependent improvement in swallowing[28]. The injected cells still carry the mutation and may be susceptible to the same OPMD phenotype

Methods

Results

Conclusion