Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial
Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial
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DOI：
10.1089/hum.2008.107
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发表时间：
2008-10-01
影响因子：
4.2
通讯作者：
Jacobson, Samuel G.
中科院分区：
文献类型：
--
作者：
Hauswirth, William W.;Aleman, Tomas S.;Jacobson, Samuel G.
莱伯先天性黑蒙（LCA）是一组无法治愈的常染色体隐性致盲视网膜疾病。一种分子形式是由RPE 65（视网膜色素上皮特异性65-kDa）基因突变引起的。重组腺相关病毒血清型2（rAAV 2）载体，改变携带人RPE 65基因（rAAV 2-CBSB-hRPE 65），恢复视力的动物模型与RPE 65缺陷。设计临床试验以评估rAAV 2-CBSB-hRPE 65在患有RPE 65-LCA的受试者中的安全性。三名患有RPE 65-LCA的年轻人（年龄21-24岁）接受单眼视网膜下注射150 μ l中的5.96 × 10（10）个载体基因组，并进行90天的随访检查。通过临床眼科检查评估眼部安全性（主要结局）。通过视力和暗适应全视野敏感度测试（FST）测量视功能;通过光学相干断层扫描（OCT）监测视网膜中央结构。未检测到与载体相关的严重不良事件或全身毒性。视力与基线相比无显著差异; 1例患者OCT显示中心凹视网膜变薄。所有患者均自我报告研究眼与对照眼相比视觉灵敏度增加，尤其是在环境光线减弱的条件下。比较基线和治疗后30-90天的暗适应FST结果。对于研究眼，灵敏度从平均基线增加是高度显著的（p < 0.001）;而对于对照眼，灵敏度变化不显著（p = 0.99）。比较目前的工作和其他两项研究的眼部基因治疗RPE 65-LCA的同时进行，并报告。
Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form is caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry the human RPE65 gene (rAAV2-CBSB-hRPE65), restored vision in animal models with RPE65 deficiency. A clinical trial was designed to assess the safety of rAAV2-CBSB-hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21-24 years) with RPE65-LCA received a uniocular subretinal injection of 5.96 X 10(10) vector genomes in 150 mu l and were studied with follow-up examinations for 90 days. Ocular safety, the primary outcome, was assessed by clinical eye examination. Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing (FST); central retinal structure was monitored by optical coherence tomography (OCT). Neither vector-related serious adverse events nor systemic toxicities were detected. Visual acuity was not significantly different from baseline; one patient showed retinal thinning at the fovea by OCT. All patients self-reported increased visual sensitivity in the study eye compared with their control eye, especially noticeable under reduced ambient light conditions. The dark-adapted FST results were compared between baseline and 30-90 days after treatment. For study eyes, sensitivity increases from mean baseline were highly significant (p < 0.001); whereas, for control eyes, sensitivity changes were not significant (p = 0.99). Comparisons are drawn between the present work and two other studies of ocular gene therapy for RPE65-LCA that were carried out contemporaneously and reported.