Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A

被引：54

作者：

Bartoli, M ^{[1
]}

Roudaut, C ^{[1
]}

Martin, S ^{[1
]}

Fougerousse, F ^{[1
]}

Suel, L ^{[1
]}

Poupiot, J ^{[1
]}

Gicquel, E ^{[1
]}

Noulet, F ^{[1
]}

Danos, O ^{[1
]}

Richard, I ^{[1
]}

机构：

[1] Genethon, CNRS, UMR8115, F-91000 Evry, France

来源：

MOLECULAR THERAPY | 2006年 / 13卷 / 02期

关键词：

limb girdle muscular dystrophy type 2A; gene transfer; calpain; 3; AAV; muscle;

D O I：

10.1016/j.ymthe.2005.09.017

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Calpainopathy (limb-girdle muscular dystrophy type 2A, LGMD2A) is a recessive muscular disorder caused by deficiency in the calcium-dependent cysteine protease calpain 3. To date, no treatment exists for this disease. We evaluated the potential of recombinant adeno-associated virus (rAAV) vectors for gene therapy in a murine model for LGMD2A. To drive the expression of calpain 3, we used rAAV2/1 pseudotyped vectors and muscle-specific promoters to avoid calpain 3 cell toxicity. We report efficient and stable transgene expression in muscle with restoration of the proteolytic activity and without evident toxicity. In addition, calpain 3 was correctly targeted to the sarcomere. Moreover, its presence resulted in improvement of the histological features and in therapeutic efficacy at the physiological levels, including correction of atrophy and full rescue of the contractile force deficits. Our results establish the feasibility of AAV-mediated calpain 3 gene transfer as a therapeutic approach.

引用

页码：250 / 259

页数：10

共 38 条

[1] Characterization of monoclonal antibodies to calpain 3 and protein expression in muscle from patients with limb-girdle muscular dystrophy type 2A [J].