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Nat Commun ; 8: 14848, 2017 03 31.
Article in English | MEDLINE | ID: mdl-28361972

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.


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