Myosin7a deficiency results in reduced retinal activity which is improved by gene therapy.
Myosin7a deficiency results in reduced retinal activity which is improved by gene therapy.
复制标题
DOI：
10.1371/journal.pone.0072027
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Auricchio A
中科院分区：
文献类型：
--
作者：
Colella P;Sommella A;Marrocco E;Di Vicino U;Polishchuk E;Garcia Garrido M;Seeliger MW;Polishchuk R;Auricchio A
MYO7A 突变会导致常染色体隐性遗传 IB 型 Usher 综合征 (USH1B)，这是一种最常见的疾病，同时伴有严重先天性听力障碍和色素性视网膜炎。基因治疗是一种有前途的视网膜色素变性治疗策略，但其临床前开发受到 USH1B 的 shaker1 (sh1−/−) 小鼠模型的轻度视网膜表型的限制，该模型缺乏视网膜功能异常和变性。在这里，我们报告了 sh1−/− 光感受器从光脱敏中恢复的能力出现了显着的、早发性的延迟，并且在 12 个月龄以内的光感受器没有显着损失的情况下，b 波视网膜电图幅度和光敏感性逐渐降低。我们还表明，编码大MYO7A蛋白的AAV载体视网膜下递送至sh1−/−视网膜可导致sh1−/−光感受器和视网膜色素上皮超微结构异常的显着改善，这与光脱敏恢复的改善相关。这些发现为评估 USH1B 实验疗法的疗效提供了新工具。此外，尽管表达大基因的AAV载体由于其基因组异质性可能限制其临床应用，但我们的数据表明AAV介导的MYO7A基因转移到sh1−/−视网膜是有效的。
Mutations in MYO7A cause autosomal recessive Usher syndrome type IB (USH1B), one of the most frequent conditions that combine severe congenital hearing impairment and retinitis pigmentosa. A promising therapeutic strategy for retinitis pigmentosa is gene therapy, however its pre-clinical development is limited by the mild retinal phenotype of the shaker1 (sh1−/−) murine model of USH1B which lacks both retinal functional abnormalities and degeneration. Here we report a significant, early-onset delay of sh1−/− photoreceptor ability to recover from light desensitization as well as a progressive reduction of both b-wave electroretinogram amplitude and light sensitivity, in the absence of significant loss of photoreceptors up to 12 months of age. We additionally show that subretinal delivery to the sh1−/− retina of AAV vectors encoding the large MYO7A protein results in significant improvement of sh1−/− photoreceptor and retinal pigment epithelium ultrastructural anomalies which is associated with improvement of recovery from light desensitization. These findings provide new tools to evaluate the efficacy of experimental therapies for USH1B. In addition, although AAV vectors expressing large genes might have limited clinical applications due to their genome heterogeneity, our data show that AAV-mediated MYO7A gene transfer to the sh1−/− retina is effective.
登录
查看更多内容
影响因子：
12.4
作者：
Gargiulo, Annagiusi;Bonetti, Ciro;Surace, Enrico M.
通讯作者：
Surace, Enrico M.
DOI：
10.1073/pnas.1130432100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Gibbs, D;Kitamoto, J;Williams, DS
通讯作者：
Williams, DS
影响因子：
5.1
作者：
Grüter, O;Kostic, C;Arsenijevic, Y
通讯作者：
Arsenijevic, Y
DOI：
10.1007/978-1-4614-0631-0_61
发表时间：
2012-01-01
期刊：
RETINAL DEGENERATIVE DISEASES
影响因子：
--
作者：
Fischer, M. Dominik;Huber, Gesine;Seeliger, Mathias W.
通讯作者：
Seeliger, Mathias W.
影响因子：
4.2
作者：
KEMP, CM;JACOBSON, SG;NATHANS, J
通讯作者：
NATHANS, J