Clinical trials of gene therapy for Leber congenital amaurosis

Leber先天性黑蒙基因治疗的临床试验

• 批准号: 7071589
• 负责人: SAMUEL GREGORY JACOBSON
• 金额: $ 177.16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071589
• 关键词: aging; blindness; clinical research; clinical trial phase I; clinical trials; dogs; gene mutation; gene therapy; genes; human; vision

DESCRIPTION (provided by applicant): A two-center human clinical trial is proposed 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. LCA from RPE65 mutations is incurable but proof-of-concept studies in animals with RPE65 deficiency indicate there is potential for treatment success given delivery of 11-cis retinal to remaining photoreceptors. LCA patients with RPE65 mutations were recently proven to have sufficient similarity to the animal models in retinal structure-function relationships to warrant this phase I trial. Preclinical safety studies and regulatory approvals are ongoing and planned for completion as part of a U10 (EY13729) multi-center research/clinical grant. Four specific aims are proposed: 1) a phase I clinical trial of uniocular single dose per patient rAAV2-RPE65 in 6 subjects 18 years and older with retinopathy due to RPE65 mutations; 2) a phase I clinical trial of uniocular single dose per patient rAAV2-RPE65 in 6 subjects 13-18 years of age with retinopathy due to RPE65 mutations; 3) a phase I clinical trial of serial redosing of rAAV2-RPE65 in 6 adult and younger subjects with retinopathy due to RPE65 mutations; a single dose in one eye will be followed after an interval of 3 months by a single dose to the contralateral eye; and 4) study of newly-identified patients with RPE65 mutations of all ages to determine retinal structure-function relationships, thereby identifying further candidates for the other 3 aims and for future studies. Before and at regularly-scheduled time points after subretinal administration of the vector, ocular-retinal and systemic clinical assessments will be performed to evaluate toxicity. The clinical trials, which will be performed under the guidelines of Good Clinical Practice and within a General Clinical Research Center, are sequential and involve a dose escalation plan with appropriate intervals to allow safety analysis and conference with all regulatory bodies before proceeding. cGMP-grade vector production will be performed under appropriate FDA guidelines. Data generated from the proposed studies should test the hypothesis that this vector in these patients is safe and warrants consideration of use in further phases of clinical trials of gene therapy for LCA associated with RPE65 mutations.

描述（由申请人提供）：拟进行一项双中心人体临床试验，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。来自RPE 65突变的LCA是不可治愈的，但在RPE 65缺陷动物中进行的概念验证研究表明，如果将11-顺式视黄醇递送至剩余的光感受器，则有可能获得治疗成功。最近证明，RPE 65突变的LCA患者在视网膜结构-功能关系方面与动物模型具有足够的相似性，以保证这项I期试验。 临床前安全性研究和监管批准正在进行中，并计划作为U10（EY 13729）多中心研究/临床资助的一部分完成。提出了四个具体目的：1）在6名18岁及以上患有由RPE 65突变引起的视网膜病变的受试者中进行每名患者单眼单剂量rAAV 2-RPE 65的I期临床试验; 2）在6名13-18岁患有由RPE 65突变引起的视网膜病变的受试者中进行每名患者单眼单剂量rAAV 2-RPE 65的I期临床试验; 3）在6名患有由于RPE 65突变引起的视网膜病变的成人和年轻受试者中连续再给药rAAV 2-RPE 65的I期临床试验;在一只眼睛中的单次剂量将在3个月的间隔之后通过对侧眼睛的单次剂量跟随;和4）研究所有年龄的新鉴定的具有RPE 65突变的患者，以确定视网膜结构-功能关系，从而为其他3个目的和未来的研究鉴定进一步的候选者。在视网膜下施用载体之前和之后的定期安排的时间点，将进行眼-视网膜和全身临床评估以评价毒性。临床试验将根据药物临床试验质量管理规范的指导原则在一般临床研究中心内进行，是连续的，涉及适当间隔的剂量递增计划，以便在继续进行之前进行安全性分析并与所有监管机构进行会议。cGMP级载体生产将根据适当的FDA指南进行。从拟议的研究中产生的数据应该测试的假设，这种载体在这些患者是安全的，并保证考虑在进一步阶段的临床试验中使用的基因治疗与RPE 65突变相关的LCA。