Clinical trials of gene therapy for Leber congenital amaurosis

Leber先天性黑蒙基因治疗的临床试验

基本信息

批准号：
7665324
负责人：
SAMUEL GREGORY JACOBSON
金额：
$ 78.28万
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7665324
关键词：
11 cis Retinal 18 year old 1p31 Adult Affect Age Amino Acids Animal Diseases Animal Model Animals Apoptotic Biochemical Blindness Canis familiaris Cell Death Cell Transplantation Cells Chromosomes Clinic Clinical Clinical Research Clinical Trials Clinical Trials Data Monitoring Committees Clinical assessments Contralateral Cyclic GMP Data Defect Degenerative Disorder Diagnosis Disease Dose Electroretinography Enrollment Ensure Eye Florida Funding Future Gene Delivery Gene Transfer Genes Goals Grant Guidelines Human Image Inherited Intervention Knock-out Laboratories Leber&apos s amaurosis Measurement Measures Modeling Mus Mutant Strains Mice Mutation Outcome Outcome Measure Patients Pennsylvania Phase Phase I Clinical Trials Photoreceptors Preparation Prevention Production Proteins Recombinant adeno-associated virus (rAAV)Recommendation Research Research Ethics Committees Resolution Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinal Pigments Retinoids Rodent Safety Schedule Site Structure Structure of retinal pigment epithelium Structure-Activity Relationship Testing Time Toxic effect Translations Universities Vision Visual Visual Acuity Work adeno-associated viral vector base blind chromophore clinical practice cohort design dosage early onset gene function gene therapy gene therapy clinical trial in vivo instrument man mutant nonhuman primate open label pre-clinical preclinical safety preclinical study research study restoration retinal rods safety study success symposium theories vector visual cycle young adult

项目摘要

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）：提出了一项两中心的人类临床试验，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（RPE65）（视网膜色素上皮上皮protecific Protecific Protecific Protinecific Protinein 655-kda）。 RPE65突变的LCA是无法治愈的，但是在RPE65缺乏症的动物中的概念验证研究表明，鉴于递送11盘视网膜到剩余的光感受器的递送，有可能获得治疗成功。最近证明，患有RPE65突变的LCA患者与视网膜结构功能关系中的动物模型具有足够的相似性，以保证该阶段I期试验。作为U10（EY13729）多中心研究/临床赠款的一部分，临床前安全研究和监管批准正在进行并计划完成。提出了四个具体目的：1）在18岁以上的6名受试者中，每名患者RAAV2-RPE65单位剂量的I期临床试验因RPE65突变而患有视网膜病变； 2）每位患者RAAV2-RPE65单位剂量的I期临床试验，在6名受试者中为13-18岁，因RPE65突变而患有视网膜病变； 3）I期由于RPE65突变引起的6名成人和年轻受试者的RAAV2-RPE65系列延长的临床试验；一只眼睛的单一剂量将在3个月间隔后与对侧眼睛进行一次剂量。 4）研究所有年龄段的RPE65突变的新识别患者，以确定视网膜结构 - 功能关系，从而确定其他3个目标和未来研究的进一步候选者。视网膜下给予载体后的定期分组时间点，将进行眼视网膜和全身临床评估以评估毒性。该临床试验将根据良好的临床实践和一般临床研究中心的指南进行，是顺序的，涉及适当间隔的剂量升级计划，以允许在进行之前与所有监管机构进行安全分析和会议。 CGMP级矢量生产将根据适当的FDA指南进行。根据拟议的研究产生的数据应检验以下假设：这些患者中的该载体是安全的，并需要考虑在与RPE65突变相关的LCA临床试验的进一步阶段使用。