Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.
Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.
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DOI：
10.1001/archophthalmol.2011.298
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发表时间：
2012-01
影响因子：
--
通讯作者：
Hauswirth, William W.
中科院分区：
文献类型：
--
作者：
Jacobson, Samuel G.;Cideciyan, Artur V.;Ratnakaram, Ramakrishna;Heon, Elise;Schwartz, Sharon B.;Roman, Alejandro J.;Peden, Marc C.;Aleman, Tomas S.;Boye, Sanford L.;Sumaroka, Alexander;Conlon, Thomas J.;Calcedo, Roberto;Pang, Ji-Jing;Erger, Kirsten E.;Olivares, Melani B.;Mullins, Cristina L.;Swider, Malgorzata;Kaushal, Shalesh;Feuer, William J.;Iannaccone, Alessandro;Fishman, Gerald A.;Stone, Edwin M.;Byrne, Barry J.;Hauswirth, William W.
确定使用携带人RPE 65基因的重组腺相关病毒2（rAAV 2）对RPE 65型Leber先天性黑蒙进行视网膜下基因治疗的安全性和有效性。在视网膜下注射rAAV 2-hRPE 65至功能更差的眼睛后评估的15名患者（11-30岁）的开放标签、剂量递增I期研究。5个队列代表4个剂量水平和2种不同的注射策略。主要结局为全身和眼部安全性。次要结果用暗适应全视野敏感度测试和ETDRS视力测定视功能。进一步的试验包括对载体的免疫反应、静态视野、瞳孔测量、移动性能和OCT。未检测到全身毒性;眼部不良事件与手术相关。所有患者的视功能均有不同程度的改善;改善局限于治疗区域。研究眼的视锥细胞和视杆细胞敏感性显著增加，但对照眼无此现象。在许多研究和对照眼中记录了轻微的视力改善。主要的视力改善发生在最低的入口视力和视网膜旁固定位点治疗视网膜下注射的研究眼睛。其他中心凹结构较好的患者在中心凹下注射后视网膜厚度和视力下降。RPE 65-LCA基因治疗对中心凹外视网膜是足够安全和基本有效的。治疗中央凹没有好处，而且有一定的风险。没有发现年龄依赖性效应的证据，我们的研究结果为后续阶段提供了具体的治疗策略。遗传性视网膜疾病的基因治疗有可能成为未来临床实践的一部分。
To determine safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying human RPE65 gene. Open-label, dose-escalation Phase I study of 15 patients (11-30 years) evaluated after subretinal injection of rAAV2-hRPE65 to the worse-functioning eye. Five cohorts represented four dose levels and two different injection strategies. Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and ETDRS visual acuity. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance and OCT. No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in study eyes but not control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections. RPE65-LCA gene therapy is sufficiently safe and substantially efficacious to the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases. Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice.
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影响因子：
4.2
作者：
Cideciyan, Artur V.;Hauswirth, William W.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.
RPE65的慢病毒基因转移在Leber先天性amurosis小鼠模型中挽救了锥体的生存和功能。
影响因子：
15.8
作者：
Bemelmans, Alexis-Pierre;Kostic, Corinne;Crippa, Sylvain V.;Hauswirth, William W.;Lem, Janis;Munier, Francis L.;Seeliger, Mathias W.;Wenzel, Andreas;Arsenijevic, Yvan
通讯作者：
Arsenijevic, Yvan
影响因子：
4.4
作者：
Chen, Y;Moiseyev, Q;Ma, JX
通讯作者：
Ma, JX
影响因子：
1.4
作者：
Geruschat, DR;Turano, KA;Stahl, JW
通讯作者：
Stahl, JW
影响因子：
4.4
作者：
Aleman, TS;Jacobson, SG;Cideciyan, AV
通讯作者：
Cideciyan, AV