Clinical Trials of Gene Therapy for Leber Congenital Amaurosis

莱伯先天性黑蒙基因治疗的临床试验

基本信息

批准号：
8323431
负责人：
SAMUEL GREGORY JACOBSON
金额：
$ 60.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323431
关键词：
Address Affect Aftercare Animal Model Architecture Blindness Canis familiaris Clinic Clinical Trials Dark Adaptation Data Defect Degenerative Disorder Development Disease Dose Enrollment Eye Future Gene Delivery Genes Genetic Grant Health Human Human Genetics Injection of therapeutic agent Intervention Kinetics Laboratories Lead Leber&apos s amaurosis Lighting Location Longevity Medical Modeling Movement Mus Mutation Natural History Operative Surgical Procedures Orphan Pathway interactions Patients Performance Phase Photoreceptors Play Principal Investigator Procedures Property Proteins Recombinant adeno-associated virus (rAAV)Reporting Research Personnel Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinal Pigments Retinoids Role Safety Site Source Structure Structure of retinal pigment epithelium Time Toxicity Tests Vertebrate Photoreceptors Viral Vector Vision Visual Visual Fields adeno-associated viral vector age group base cohort expectation follow-up fovea centralis gene therapy gene therapy clinical trial human disease improved research study response retinal rods sample fixation subretinal injection success treatment duration treatment effect vector visual cycle

项目摘要

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.

描述（由申请人提供）：已经进行了第一个人类临床试验，以评估基于雷伯先天性症状（LCA）失明患者的重组腺相关病毒（RAAV）载体的基因递送的基因和RPE65中突变的视网膜的安全性。视力在RPE65-LCA（一种先前无法治疗且无法治愈的人类视网膜退行性疾病）中安全恢复。在当前赠款期结束时，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名代表两个年龄组的患者：8-17（n = 7）和> 18岁（n = 8）：一只眼睛中的一个单个注射部位（同一眼睛的1-3，n = 9）和两个眼部的注射位点，在同一手术中（COHORTS 4和COHORTS 4和4和5，N = 6）。现在提出了五个具体目标来完成这项早期阶段试验。 AIM 1-评估所有15名受试者的视网膜下RAAV2-HRPE65基因治疗的长期安全性，其中FDA规定了三年的随访。目标2-通过确定基因疗法恢复视力的功效：a）如果早期视力在治疗后3年持续存在； b）治疗前光感受器RPE结构是否可以预测治疗后视觉敏感性的提高； c）如果在治疗后发生了更长的时间课程中出现的视觉变化。目标3-评估基因治疗是否通过确定来改变视网膜变性的自然历史：a）人类RPE65-LCA的自然病史仅在仅圆锥体中央凹和杆主的外牛外视网膜中； b）如果经过处理的视网膜区域具有不同的感光体损失的自然病史。 AIM 4-研究使用深色适应测定法对治疗患者的恢复视觉周期的特性，并确定：a）是否有适应缺陷的剂量反应函数； b）杆和锥体的最终速率动力学是剩余的感光体结构和视网膜位置，治疗前视觉功能以及治疗后改善程度的函数； c）如果黑暗适应缺陷随着治疗后的时间而变化。 AIM 5-评估迁移性能是否受基因治疗干预的影响以及什么量化视觉参数会影响迁移率。因此，将向这15名患者的程序引起的许多科学和医学问题寻求答案。这些答案应完善该方法并阐明对这种疾病中基因疗法的期望，并为其他人类遗传性视网膜疾病提供更好的方法，这些疾病将排队作为这种类型的治疗的未来候选人。相关性：当前的提案与正在进行的临床试验相吻合。关于遗传性视网膜疾病的第一种人基因疗法的详细结果仍然存在许多未解决的问题。这笔赠款的五个目标既是监管和科学的，又将寻求答案，以进一步发展这项临床试验和视网膜退行性疾病的未来基因治疗试验至关重要的问题。