PABPN1 gene therapy for oculopharyngeal muscular dystrophy

被引：49

作者：

Malerba, A. ^{[1
]}

Klein, P. ^{[2
]}

Bachtarzi, H. ^{[1
]}

Jarmin, S. A. ^{[1
]}

Cordova, G. ^{[2
]}

Ferry, A. ^{[2
,3
]}

Strings, V. ^{[4
]}

Espinoza, M. Polay ^{[2
]}

Mamchaoui, K. ^{[2
]}

Blumen, S. C. ^{[5
]}

St Guily, J. Lacau ^{[2
,6
,7
]}

Mouly, V. ^{[2
]}

Graham, M. ^{[4
]}

Butler-Browne, G. ^{[2
]}

Suhy, D. A. ^{[4
]}

Trollet, C. ^{[2
]}

Dickson, G. ^{[1
]}

机构：

[1] Univ London, Royal Holloway, Sch Biol Sci, Egham Hill, Egham TW20 0EX, Surrey, England

[2] UPMC Univ Paris 06, Sorbonne Univ, INSERM, CNRS,Inst Myol,FRE3617,UM76,U974, 47 Bd Hop, F-75013 Paris, France

[3] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France

[4] Benitec Biopharma, 3940 Trust Way, Hayward, CA 94545 USA

[5] Technion, Hadera & Rappaport Fac Med, Hillel Yaffe Med Ctr, Dept Neurol, 1 Efron St, IL-31096 Haifa, Israel

[6] Fac Med, Dept Otolaryngol Head & Neck Surg, F-75252 Paris, France

[7] Univ Pierre & Marie Curie Paris VI, Tenon Hosp, AP HP, F-75252 Paris, France

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

POLY(A) BINDING-PROTEIN; MEDIATED RNA INTERFERENCE; PRE-MESSENGER-RNA; INTRANUCLEAR INCLUSIONS; NUCLEAR INCLUSIONS; MOUSE MODEL; MUSCLE; AGGREGATION; CHAPERONES; TOXICITY;

D O I：

10.1038/ncomms14848

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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