PABPN1 gene therapy for oculopharyngeal muscular dystrophy

A. Malerba, P. Klein, H. Bachtarzi, S. A. Jarmin, G. Cordova, A. Ferry, V. Strings, M. Polay Espinoza, K. Mamchaoui, S. C. Blumen, J. Lacau St Guily, V. Mouly, M. Graham, G. Butler-Browne, D. A. Suhy, C. Trollet () and G. Dickson ()
Additional contact information
A. Malerba: School of Biological Sciences, Royal Holloway, University of London, Egham Hill
P. Klein: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
H. Bachtarzi: School of Biological Sciences, Royal Holloway, University of London, Egham Hill
S. A. Jarmin: School of Biological Sciences, Royal Holloway, University of London, Egham Hill
G. Cordova: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
A. Ferry: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
V. Strings: Benitec Biopharma
M. Polay Espinoza: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
K. Mamchaoui: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
S. C. Blumen: Hillel Yaffe Medical Center, Hadera and Rappaport Faculty of Medicine, The Technion
J. Lacau St Guily: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
V. Mouly: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
M. Graham: Benitec Biopharma
G. Butler-Browne: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
D. A. Suhy: Benitec Biopharma
C. Trollet: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
G. Dickson: School of Biological Sciences, Royal Holloway, University of London, Egham Hill

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14848

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