Service de Médecine Interne 1, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
Brain. 2012 Feb;135(Pt 2):483-92. doi: 10.1093/brain/awr342. Epub 2012 Jan 11.
γ-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the γ-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27 years; range 16-38 years) with del525T homozygous mutation of the γ-sarcoglycan gene and no γ-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 γ-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 × 10(9) viral genomes in 100 µl, the second group received a single injection of 1.5 × 10(10) viral genomes in 100 µl, and the third group received three simultaneous 100-µl injections at the same site, delivering a total dose of 4.5 × 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 γ-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 γ-sarcoglycan messenger RNA. In one patient, γ-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of γ-sarcoglycan expression (<1% positively stained fibres) were also detectable. Expression of γ-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.
γ- 横纹肌营养不良症或肢带型肌营养不良症 2C 型是一种无法治愈的疾病，由 γ- 横纹肌聚糖基因的常染色体隐性遗传突变引起。9 名不能行走的患者（2 名男性，7 名女性，平均年龄 27 岁；范围 16-38 岁）携带 γ- 横纹肌聚糖基因的 del525T 纯合突变，肌肉活检中无 γ- 横纹肌聚糖免疫染色，将携带肌球蛋白启动子控制的人 γ- 横纹肌聚糖基因的腺相关病毒血清型 1 载体分为三组，每组接受三种递增剂量，通过局部注射到伸腕肌中。第一组接受 3×10(9)个病毒基因组，体积为 100μl；第二组接受 1.5×10(10)个病毒基因组，体积为 100μl；第三组在同一部位同时接受 3 次 100μl 注射，总剂量为 4.5×10(10)个病毒基因组。在 6 个月的随访期间没有发生严重的不良反应。9 名患者均成为腺相关病毒血清型 1 血清阳性，1 名患者对腺相关病毒血清型 1 衣壳产生细胞毒性反应。30 天后，对接受最高剂量（4.7-10.5%染色阳性纤维）的 3 名患者的注射肌肉活检标本进行免疫组织化学分析，发现 γ- 横纹肌聚糖表达，而实时聚合酶链反应检测到 γ- 横纹肌聚糖信使 RNA。在 1 名患者中，通过 Western blot 检测到 γ- 横纹肌聚糖蛋白。对于接受低剂量和中剂量的另外 2 名患者，也可以检测到离散水平的 γ- 横纹肌聚糖表达（<1%染色阳性纤维）。腺相关病毒血清型 1 基因转移可诱导肢带型肌营养不良症 2C 患者表达 γ- 横纹肌聚糖蛋白，无严重不良反应。
