title: PABPN1 gene therapy for oculopharyngeal muscular dystrophy.
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.
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham Hill, Egham, TW20 0EX Surrey, UK.
authors.forename: A
authors.initials: A
authors.lastname: Malerba
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Klein
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham Hill, Egham, TW20 0EX Surrey, UK.
authors.forename: H
authors.initials: H
authors.lastname: Bachtarzi
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham Hill, Egham, TW20 0EX Surrey, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Jarmin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Cordova
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Benitec Biopharma, 3940 Trust Way, Hayward, California 94545, USA.
authors.forename: V
authors.initials: V
authors.lastname: Strings
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: M Polay
authors.initials: MP
authors.lastname: Espinoza
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Mamchaoui
authors.affiliation: Department of Neurology, Hillel Yaffe Medical Center, Hadera and Rappaport Faculty of Medicine, The Technion, 1 Efron Street, Haifa 31096, Israel.
authors.forename: S C
authors.initials: SC
authors.lastname: Blumen
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.|Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine and University Pierre-et-Marie-Curie, Paris VI, Tenon Hospital, Assistance Publique des Hopitaux de Paris, 75252 Paris, France.
authors.forename: J Lacau
authors.initials: JL
authors.lastname: St Guily
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Mouly
authors.affiliation: Benitec Biopharma, 3940 Trust Way, Hayward, California 94545, USA.
authors.forename: M
authors.initials: M
authors.lastname: Graham
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Butler-Browne
authors.affiliation: Benitec Biopharma, 3940 Trust Way, Hayward, California 94545, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Suhy
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l'Hôpital, 75013 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Trollet
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London, Egham Hill, Egham, TW20 0EX Surrey, UK.
authors.forename: G
authors.initials: G
authors.lastname: Dickson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D053580:Muscle Strength / Q000235:genetics*; D039141:Muscular Dystrophy, Oculopharyngeal / Q000503:physiopathology / Q000628:therapy*; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D039122:Poly(A)-Binding Protein I / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: D039122:Poly(A)-Binding Protein I