Clinical Trials of Gene Therapy for Leber Congenital Amaurosis

描述(申请人提供)：已经进行了第一项人类临床试验，以评估基于重组腺相关病毒(RAAV)载体的基因转移到Leber先天性黑色素瘤(LCA)失明患者和RPE65(视网膜色素上皮特定蛋白65-kDa)基因突变患者的安全性。RPE65-LCA的视力安全恢复，这是一种以前无法治疗和不可治愈的人类视网膜退行性疾病。在目前的资助期结束时，我们将治疗15名患者，分别代表两个年龄段：8-17岁(n=7)和18岁(n=8)，使用4种不同的剂量和两种方法：一只眼睛的单一注射地点(队列1-3，n=9)和同一手术期间的一只眼睛的两个注射地点(队列4和5，n=6)。现在提出了完成这一早期阶段试验的五个具体目标。目的1-评估视网膜下rAAV2-hRPE65基因治疗在所有15名受试者中的长期安全性，FDA规定的随访时间为3年。目的2-评估基因治疗恢复视力的有效性，方法是确定：a)早期视力改善是否持续到治疗后3年；b)治疗前的光感受器-RPE结构是否预示着治疗后视觉敏感度的改善；以及c)治疗后是否出现较长时间的视觉变化。目的3-评估基因治疗是否改变了视网膜变性的自然历史，方法是确定：a)人类RPE65-LCA在仅视锥中心凹和视杆细胞支配的中心凹外视网膜中的视网膜变性的自然历史；以及b)被治疗的视网膜区域是否有不同的光感受器丧失的自然历史。目的用暗适应测量法研究接受治疗的患者恢复的视觉周期的特征，并确定：a)适应缺陷是否存在剂量-反应函数；b)视杆和视锥的速率动力学随剩余的光感受器结构和视网膜位置、治疗前的视功能和治疗后的改善程度而变化；以及c)暗适应缺陷是否随治疗后的时间而变化。目的5-评估基因治疗干预是否影响患者的活动能力，以及哪些量化的视觉参数对活动能力有影响。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。这些答案应该改进方法并澄清对这种疾病的基因治疗的期望，并导致对其他人类遗传性视网膜疾病的更好方法，这些疾病正在排队作为未来这种类型的治疗的候选者。相关性：目前的建议与正在进行的临床试验相吻合。关于首个针对遗传性视网膜疾病的人类基因疗法的详细结果，仍有许多悬而未决的问题。这笔赠款的五个目标既是监管的，也是科学的，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的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.