A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C

被引：66

作者：

Herson, Serge

Hentati, Faycal ^{[1
]}

Rigolet, Aude

Behin, Anthony ^{[2
]}

Romero, Norma B. ^{[2
]}

Leturcq, France ^{[3
]}

Laforet, Pascal ^{[2
]}

Maisonobe, Thierry ^{[2
]}

Amouri, Rim ^{[1
]}

Haddad, Hafedh ^{[4
]}

Audit, Muriel ^{[5
]}

Montus, Marie ^{[4
]}

Masurier, Carole ^{[4
]}

Gjata, Bernard ^{[4
]}

Georger, Christophe ^{[4
]}

Cherai, Mustapha ^{[6
]}

Carlier, Pierre ^{[2
]}

Hogrel, Jean-Yves ^{[2
]}

Herson, Ariane ^{[2
]}

Allenbach, Yves

Lemoine, Francois M. ^{[6
]}

Klatzmann, David ^{[6
]}

Sweeney, H. Lee ^{[7
]}

Mulligan, Richard C. ^{[8
]}

Eymard, Bruno ^{[2
]}

Caizergues, Didier ^{[4
]}

Voit, Thomas ^{[2
]}

Benveniste, Olivier

机构：

[1] Natl Inst Neurol, Dept Mol Neurobiol & Neuropathol, Tunis 1007, Tunisia

[2] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, Inst Myol, F-75013 Paris, France

[3] Hop Cochin, AP HP, Biochim Genet Lab, F-75014 Paris, France

[4] Genethon, F-91000 Evry, France

[5] Genosafe, F-91000 Evry, France

[6] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, CNRS UMR 7211, F-75013 Paris, France

[7] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA

[8] Harvard Univ, Sch Med, Dept Genet, Harvard Gene Therapy Initiat, Boston, MA 02115 USA

来源：

BRAIN | 2012年 / 135卷

关键词：

adeno-associated virus; gene transfer; muscular dystrophy; SKELETAL-MUSCLE; EXPRESSION; SARCOGLYCANOPATHY; HEMOPHILIA; PHENOTYPE; DISEASE; SAFETY;

D O I：

10.1093/brain/awr342

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

gamma-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the gamma-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27 years; range 16-38 years) with del525T homozygous mutation of the gamma-sarcoglycan gene and no gamma-sarcoglycan immunostaining on muscle biopsy were divided into three equal groups to receive three escalating doses of an adeno-associated virus serotype 1 vector expressing the human gamma-sarcoglycan gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3 x 10(9) viral genomes in 100 mu l, the second group received a single injection of 1.5 x 10(10) viral genomes in 100 mu l, and the third group received three simultaneous 100-mu l injections at the same site, delivering a total dose of 4.5 x 10(10) viral genomes. No serious adverse effects occurred during 6 months of follow-up. All nine patients became adeno-associated virus serotype 1 seropositive and one developed a cytotoxic response to the adeno-associated virus serotype 1 capsid. Thirty days later, immunohistochemical analysis of injected-muscle biopsy specimens showed gamma-sarcoglycan expression in all three patients who received the highest dose (4.7-10.5% positively stained fibres), while real-time polymerase chain reaction detected gamma-sarcoglycan messenger RNA. In one patient, gamma-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of gamma-sarcoglycan expression (< 1% positively stained fibres) were also detectable. Expression of gamma-sarcoglycan protein can be induced in patients with limb girdle muscular dystrophy type 2C by adeno-associated virus serotype 1 gene transfer, with no serious adverse effects.

引用

页码：483 / 492

页数：10

共 31 条

[1] Effect of gene therapy on visual function in Leber's congenital amaurosis [J].