Clinical Trials of Gene Therapy for Leber Congenital Amaurosis

描述（由申请人提供）：首次人体临床试验已经进行，以评估重组腺相关病毒（rAAV）载体为基础的基因递送到Leber先天性黑内障（LCA）失明患者视网膜和RPE65（视网膜色素上皮特异性蛋白65-kDa）基因突变的安全性。RPE65-LCA患者视力安全恢复，这是一种以前无法治疗和无法治愈的人类视网膜退行性疾病。在本资助期结束时，我们将治疗15名患者，代表两个年龄组：8-17岁（n=7）和18岁（n=8），使用4种不同的剂量和两种方法：在同一手术期间在一只眼睛进行单注射（队列1-3，n=9）和在一只眼睛进行两个注射（队列4和5，n=6）。现在提出了完成这一早期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，并进行fda规定的三年随访。目的2-评估基因治疗恢复视力的效果，通过确定：a)治疗后3年早期视力改善是否持续；b)治疗前光感受器- rpe结构能否预测治疗后视敏度的改善；c)如果在治疗后较长时间内出现视觉变化。目的3-评估基因治疗是否改变视网膜变性的自然史，通过确定：a)人类RPE65-LCA视网膜变性的自然史，在只有锥体的中央凹和在杆状主导的中央凹外视网膜；b)如果接受治疗的视网膜区域有不同的光感受器丧失的自然历史。目的4-使用暗适应仪研究治疗患者恢复的视觉周期的特性，并确定：a)是否存在适应缺陷的剂量-反应函数；B)视杆细胞和视锥细胞的速率动力学与剩余光感受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关系；c)处理后暗适应缺陷是否随时间变化。目的5-评估活动能力是否受到基因治疗干预的影响，以及哪些量化的视觉参数对活动能力产生影响。因此，将为这15名患者的手术过程中产生的许多科学和医学问题寻求答案。这些答案应该改进方法，澄清对这种疾病的基因治疗的期望，并导致更好的方法来治疗其他人类遗传性视网膜疾病，这些疾病正在排队作为这种治疗的未来候选者。相关性：目前的建议与正在进行的临床试验相吻合。许多未解决的问题仍然是关于这个人类基因治疗遗传性视网膜疾病的详细结果。这项拨款的五个目的是监管和科学，并将寻求答案的关键问题，进一步发展该临床试验和视网膜退行性疾病的未来基因治疗试验。

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.