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：
7940930
负责人：
SAMUEL GREGORY JACOBSON
金额：
$ 131.33万
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7940930
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 Good Clinical Practice 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 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）：拟开展一项两中心人体临床试验，以评估基于重组腺相关病毒（rAAV）载体的基因递送至莱伯先天性黑蒙（LCA）和突变失明患者视网膜的安全性位于 RPE65（视网膜色素上皮特异性蛋白 65-kDa）基因中。 RPE65 突变引起的 LCA 无法治愈，但对 RPE65 缺陷动物进行的概念验证研究表明，如果将 11-顺式视网膜传递到剩余的光感受器，治疗有可能成功。最近证明，携带 RPE65 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，值得进行这一 I 期试验。临床前安全性研究和监管审批正在进行中，并计划作为 U10 (EY13729) 多中心研究/临床拨款的一部分完成。提出了四个具体目标：1）在 6 名 18 岁及以上因 RPE65 突变导致视网膜病变的受试者中进行单眼单剂量 rAAV2-RPE65 的 I 期临床试验； 2) 在 6 名 13-18 岁因 RPE65 突变导致视网膜病变的受试者中进行每名患者单眼单剂量 rAAV2-RPE65 的 I 期临床试验； 3) 在 6 名因 RPE65 突变而患有视网膜病变的成人和年轻受试者中连续重新给药 rAAV2-RPE65 的 I 期临床试验；一只眼单次给药，间隔 3 个月后，对侧眼睛单次给药； 4) 对新发现的所有年龄段的 RPE65 突变患者进行研究，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。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估毒性。临床试验将在药品临床试验质量管理规范的指导下，在综合临床研究中心内进行，是连续进行的，并涉及剂量递增计划，并有适当的时间间隔，以便进行安全性分析并在进行之前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。拟议研究产生的数据应检验这一假设，即该载体在这些患者中是安全的，并值得考虑在与 RPE65 突变相关的 LCA 基因治疗临床试验的进一步阶段中使用。