Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence.
Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence.
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DOI：
10.2147/opth.s231804
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Weng CY
中科院分区：
文献类型：
--
作者：
Gao J;Hussain RM;Weng CY
视网膜下基因治疗试验始于RPE65变异的发现及其与Leber先天性黑色素的关联。RPE65蛋白对视觉光转导级联的正常功能至关重要。建立了RPE65基因敲除动物模型，并显示出与人类同类动物相似的疾病表型。在这些使用视网膜下RPE65基因替代疗法的动物模型中进行了概念性研究，结果改善了各种视觉功能标记物，包括视网膜电信号、瞳孔光反应和物体回避行为。动物模型的阳性结果导致使用腺相关病毒载体的第一阶段人类研究。这些初步的人体研究结果也显示了对视觉功能和可接受的安全性的积极影响。在剂量递增研究证实其有效性和安全性后，Spark Treeutics随后使用1.5x1011载体基因组剂量进行了里程碑式的3期研究。多亮度迁移率测试被用于测量主要疗效终点，因为它在检测遗传性视网膜疾病的进展方面具有极好的可靠性。在这项研究达到其主要终点后，美国食品和药物管理局批准voretgene neparvovec(Luxturna®)用于治疗与RPE65相关的遗传性视网膜疾病。
Subretinal gene therapy trials began with the discovery of RPE65 variants and their association with Leber congenital amaurosis. The RPE65 protein is critical for the normal functioning of the visual phototransduction cascade. RPE65 gene knockout animal models were developed and showed similar diseased phenotypes to their human counterparts. Proof of concept studies were carried out in these animal models using subretinal RPE65 gene replacement therapy, resulting in improvements in various visual function markers including electroretinograms, pupillary light responses, and object avoidance behaviors. Positive results in animal models led to Phase 1 human studies using adeno-associated viral vectors. Results in these initial human studies also showed positive impact on visual function and acceptable safety. A landmark Phase 3 study was then conducted by Spark Therapeutics using a dose of 1.5 x1011 vector genomes after dose-escalation studies confirmed its efficacy and safety. Multi-luminance mobility testing was used to measure the primary efficacy endpoint due to its excellent reliability in detecting the progression of inherited retinal diseases. After the study met its primary endpoint, the Food and Drug Administration approved voretigene neparvovec (Luxturna®) for use in RPE65-associated inherited retinal diseases.