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）载体的基因递送至因莱伯先天性黑蒙（LCA）和基因突变而失明的患者的视网膜的安全性。 RPE65（视网膜色素上皮特异性蛋白 65-kDa）基因。 RPE65-LCA（一种以前无法治愈的人类视网膜退行性疾病）的视力得到了安全恢复。在当前拨款期结束时，我们将使用 4 种不同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)：单一注射部位在同一手术过程中，一只眼睛（队列 1-3，n=9）注射一次，一只眼睛注射两个部位（队列 4 和 5，n=6）。现在提出了五个具体目标来完成这项早期试验。目标 1 - 通过 FDA 规定的三年随访，评估所有 15 名受试者视网膜下 rAAV2-hRPE65 基因治疗的长期安全性。目标 2 - 通过确定以下因素来评估基因治疗恢复视力的功效： a) 早期视力改善是否在治疗后 3 年内持续存在； 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； c) 治疗后较长时间内是否出现视力变化。目标 3- 通过确定以下因素来评估基因治疗是否改变视网膜变性的自然史： a) 人 RPE65-LCA 中仅视锥细胞中央凹和视杆细胞主导的中央凹外视网膜中视网膜变性的自然史； b) 接受治疗的视网膜区域是否具有不同的光感受器损失自然史。目标 4- 使用暗适应测定法研究治疗患者恢复的视觉周期的特性，并确定： a) 适应缺陷是否存在剂量反应函数； b) 视杆细胞和视锥细胞的最终速率动力学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； c) 治疗后暗适应缺陷是否随时间变化。目标 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会影响活动能力。因此，我们将寻求对这 15 名患者的手术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疾病的基因治疗方法并明确预期，并为其他人类遗传性视网膜疾病提供更好的方法，这些疾病正在排队作为此类治疗的未来候选者。相关性：当前的提案与正在进行的临床试验相吻合。关于第一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性的，也是科学性的，并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。