Clinical Trials of Gene Therapy for Leber Congenital Amaurosis

描述（由申请人提供）：进行了第一项人体临床试验，以评估基于重组腺相关病毒（rAAV）载体的基因递送至患有Leber先天性黑蒙（LCA）和RPE 65（视网膜色素上皮特异性蛋白65-kDa）基因突变的失明患者视网膜的安全性。RPE 65-LCA是一种以前无法治疗且无法治愈的人类视网膜退行性疾病，视力在RPE 65-LCA中得到安全恢复。在当前的资助期结束时，我们将使用4种不同的剂量和两种方法治疗代表两个年龄组的15名患者：8-17岁（n=7）和>18岁（n=8）：一只眼睛中的单个注射部位（队列1-3，n=9）和同一手术期间一只眼睛中的两个注射部位（队列4和5，n=6）。现在提出了五个具体目标，以完成这一早期阶段的试验。目的1-评估视网膜下rAAV 2-hRPE 65基因疗法在所有15名受试者中的长期安全性，具有FDA规定的三年随访。目的2-评估基因治疗恢复视力的功效，通过确定：a）视力的早期改善是否持续到治疗后3年; B）治疗前光感受器-RPE结构是否预测治疗后视觉敏感度的改善;以及c）治疗后在较长时间内是否出现视觉变化。目的3-通过确定：a）在人RPE 65-LCA中，在仅视锥中心凹和视杆为主的中心凹外视网膜中视网膜变性的自然史;和B）治疗的视网膜区域是否具有不同的光感受器损失的自然史，评价基因治疗是否改变视网膜变性的自然史。目的4-使用暗适应测定法研究治疗患者恢复的视觉周期的性质，并确定：a）是否存在适应缺陷的剂量-反应函数; B）作为剩余感光器结构和视网膜位置、治疗前视觉功能和治疗后改善程度的函数的视杆细胞和视锥细胞的所得速率动力学;和c）治疗后暗适应缺陷是否随时间变化。目的5-评估基因治疗干预是否会影响移动性能，以及哪些量化的视觉参数会影响移动性能。因此，将寻求这15名患者手术过程中出现的许多科学和医学问题的答案。这些答案应该完善这种方法，并澄清这种疾病的基因治疗的期望，并导致更好的方法，以其他人类遗传性视网膜疾病，排队作为这种类型的治疗未来的候选人。相关性：目前的提案与正在进行的临床试验相吻合。关于这第一个人类基因治疗遗传性视网膜疾病的详细结果，仍有许多悬而未决的问题。该资助的五个目标既是监管性的，也是科学性的，将寻求对进一步发展这项临床试验和未来视网膜退行性疾病基因治疗试验至关重要的问题的答案。

DESCRIPTION (provided by applicant): The first human clinical trial has been performed to assess the safety of recombinant adeno-associated virus (rAAV) vector-based gene delivery to the retina of patients with blindness from Leber congenital amaurosis (LCA) and mutations in the RPE65 (retinal pigment epithelium-specific protein 65-kDa) gene. Vision was safely restored in RPE65-LCA, a previously untreatable and incurable human retinal degenerative disease. At the end of the current grant period, we will have treated 15 patients representing two age groups: 8-17 (n=7) and >18 years (n=8), using 4 different doses and two approaches: a single injection site in one eye (Cohorts 1-3, n=9) and two injection sites in one eye at the same surgical session (Cohorts 4 and 5, n=6). Five specific aims are now proposed to complete this early phase trial. Aim 1- Evaluate the long-term safety of subretinal rAAV2-hRPE65 gene therapy in all 15 subjects with the FDA-mandated three years of follow- up. Aim 2- Evaluate the efficacy of gene therapy to restore vision by determining: a) if the early improvement in vision persists by 3 years post-treatment; b) whether pre-treatment photoreceptor-RPE structure predicts the improvement in visual sensitivity in the post-treatment period; and c) if there are visual changes that emerge over a longer time course following treatment. Aim 3- Evaluate whether gene therapy alters the natural history of retinal degeneration by determining: a) the natural history of retinal degeneration in human RPE65-LCA in the cone-only fovea and in rod-dominated extrafoveal retina; and b) if treated retinal regions have a different natural history of photoreceptor loss. Aim 4- Study the properties of the restored visual cycle in treated patients using dark adaptometry and determine: a) if there is a dose-response function for the adaptation defect; b) the resulting rate kinetics for rods and cones as a function of remaining photoreceptor architecture and retinal location, pre-treatment visual function and the extent of improvement post-treatment; and c) if the dark adaptation defect changes with time after treatment. Aim 5- Assess whether mobility performance is affected by the gene therapy intervention and what quantified visual parameters make a difference in mobility. Answers will thus be sought to the many scientific and medical questions that have arisen from the procedures in these 15 patients. These answers should refine the approach and clarify expectations of gene therapy in this disease and lead to better approaches to other human genetic retinal diseases that are queuing up as future candidates for this type of therapy. RELEVANCE: The current proposal dovetails with the ongoing clinical trial. Many unanswered questions remain about the detailed results of this first human gene therapy for a genetic retinal disease. The five aims of this grant are both regulatory and scientific and will seek answers to questions critical to further development of this clinical trial and future gene therapy trials of retinal degenerative disorders.