Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65.
Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65.
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DOI：
10.1038/gt.2016.66
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发表时间：
2016-12
期刊：
影响因子：
5.1
通讯作者：
Ali, R. R.
中科院分区：
文献类型：
--
作者：
Georgiadis, A.;Duran, Y.;Ribeiro, J.;Abelleira-Hervas, L.;Robbie, S. J.;Sunkel-Laing, B.;Fourali, S.;Gonzalez-Cordero, A.;Cristante, E.;Michaelides, M.;Bainbridge, J. W. B.;Smith, A. J.;Ali, R. R.
莱伯先天性黑朦是一组遗传性视网膜营养不良症，在儿童时期造成严重的视力损害；rpe65缺乏导致杆状光感受器功能受损从出生和锥体光感受器功能进行性损害与视网膜变性。在RPE65缺乏症的动物模型中，在视网膜下注射携带RPE65 cDNA的重组腺相关病毒（AAV） 2/2载体可改善视杆光感受器功能，并且在疾病早期进行干预可通过保护视锥光感受器免受视网膜变性提供持续的益处。在受影响的人类中，即使在视网膜变性相对轻微的情况下，这些载体的施用迄今已导致光感受器功能的相对适度改善，并且受益的持续时间受到进行性视网膜变性的限制。我们的结论是，目前的载体不能完全满足人类对RPE65的需求，并预测更强大的载体将提供更持久的效益。为此，我们修改了原始的AAV2/2载体，生成AAV2/5-OPTIRPE65。新的配置由AAV 5血清型载体组成，该载体携带优化的hRPE65启动子和密码子优化的hRPE65基因。在小鼠中，AAV2/5-OPTIRPE65的效力至少是原始AAV2/2载体的300倍。
Leber congenital amaurosis is a group of inherited retinal dystrophies that cause severe sight impairment in childhood; RPE65-deficiency causes impaired rod photoreceptor function from birth and progressive impairment of cone photoreceptor function associated with retinal degeneration. In animal models of RPE65 deficiency, subretinal injection of recombinant adeno-associated virus (AAV) 2/2 vectors carrying RPE65 cDNA improves rod photoreceptor function, and intervention at an early stage of disease provides sustained benefit by protecting cone photoreceptors against retinal degeneration. In affected humans, administration of these vectors has resulted to date in relatively modest improvements in photoreceptor function, even when retinal degeneration is comparatively mild, and the duration of benefit is limited by progressive retinal degeneration. We conclude that the demand for RPE65 in humans is not fully met by current vectors, and predict that a more powerful vector will provide more durable benefit. With this aim we have modified the original AAV2/2 vector to generate AAV2/5-OPTIRPE65. The new configuration consists of an AAV vector serotype 5 carrying an optimized hRPE65 promoter and a codon-optimized hRPE65 gene. In mice, AAV2/5-OPTIRPE65 is at least 300-fold more potent than our original AAV2/2 vector.
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影响因子：
12.4
作者：
Pang, JJ;Chang, B;Hauswirth, WW
通讯作者：
Hauswirth, WW
影响因子：
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Hauswirth, William W.
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通讯作者：
Ali, Robin R.
影响因子：
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作者：
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通讯作者：
Ali, R. R.
影响因子：
13.7
作者：
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通讯作者：
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