Biostatistics Center for Leber's Hereditary Optic Neuropathy: Gene Therapy Trial

莱伯遗传性视神经病生物统计中心：基因治疗试验

• 批准号: 8828699
• 负责人: William Jack Feuer
• 金额: $ 11.64万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828699
• 关键词: Acute; Adverse event; Affect; Antibodies; Bilateral; Biometry; Blindness; Blood; Chronic; Clinical Trials Data Monitoring Committees; Clinical Trials Design; Complex; Computers; Consent Forms; Contralateral; Data; Data Security; Development; Disease; Dose; Electrocardiogram; Eligibility Determination; Enrollment; Ensure; Exclusion Criteria; Eye; Gene therapy trial; Generations; Genes; Goals; Human; Human Resources; Inherited; Injection of therapeutic agent; Institutional Review Boards; Leber' s Hereditary Optic Neuropathy; Letters; Manuals; Masks; Maximum Tolerated Dose; Mediating; Methods; Mission; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Monitor; Mutate; Mutation; Nuclear; Outcome; Participant; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Procedures; Proteins; Protocols documentation; Recruitment Activity; Relative (related person); Reporting; Respiratory Chain; Role; Safety; Sample Size; Schedule; Secure; System; Testing; Toxic effect; Universities; Vision; Visit; Visual Acuity; Visual Fields; adeno-associated viral vector; base; body system; cohort; data management; effective therapy; efficacy trial; gene therapy; gene therapy clinical trial; implementation trial; intravitreal injection; open label; phase 2 study; programs; public health relevance; safety testing; statistics; targeted sequencing; vector

DESCRIPTION (provided by applicant): Our goal in this application is to provide biostatistical and data management support for testing safety of AAV-mediated delivery of the human ND4 gene in a phase I clinical trial of patients with mutated G11778A mtDNA and then move to a Phase II study to prove efficacy in the later years of this program. Phase I will consist of an open-label, unilateral, single-dose intravitreal injection of AAV-ND4 per patient in the worse eye in a dose-escalation study investigating the safety of three vector doses (5x10e9 vg, 2.46x10e10 vg and 1x10e11 vg) in a small number of patients with molecularly confirmed G11778A-mutated mitochondrial DNA who have chronic bilateral, severe visual loss for more than 1 year (Aim 1) or acute bilateral several visual loss for less than 1 year (Aim 2), and then, lastly, in the eye with better vision but that we know is predestined to lose significant vision within 6 months from the onset of visual loss in the first eye (Aim 3). The Biostatistics Center (BC) for Leber's Hereditary Optic Neuropathy (LHON): Gene Therapy Clinical Trial will collaborate with Dr. John Guy to implement this Phase 1 clinical trial. LHON is a maternally inherited blinding disease caused by the G11778A mutation in mitochondrial DNA that affects the ND4 gene of complex I of the respiratory chain. Our group has developed a method for allotropic expression, which is a procedure to introduce a "nuclear version" of this mitochondrial gene and to then target the cytoplasmically synthesized protein into the mitochondria with a mitochondrial targeting sequence. The role of the Biostatistics Center will be to support this tria with regard to development and implementation of trial procedures, data entry, and report generation; to confirm eligibility criteria of participants; ensure data security; and liaise with he Data and Safety Monitoring Committee.

描述（由申请人提供）：我们在本申请中的目标是提供生物统计和数据管理支持，用于在 G11778A mtDNA 突变患者的 I 期临床试验中测试 AAV 介导的人类 ND4 基因递送的安全性，然后转移到II 期研究旨在证明该计划后期的有效性。第一阶段将包括在一项剂量递增研究中，对每位患者的病情较差的眼睛进行开放标签、单侧、单剂量的 AAV-ND4 玻璃体内注射，调查三种载体剂量（5x10e9 vg、2.46x10e10 vg 和 1x10e11 vg）的安全性）在少数经分子证实线粒体 DNA G11778A 突变且患有慢性双侧严重视力丧失的患者中少于 1 年（目标 1）或急性双侧多次视力丧失少于 1 年（目标 2），最后，眼睛视力较好，但我们知道注定会在发病后 6 个月内丧失明显视力第一只眼睛的视力丧失（目标 3）。莱伯遗传性视神经病（LHON）生物统计中心（BC）：基因治疗临床试验将与 John Guy 博士合作实施这一 1 期临床试验。 LHON 是一种母系遗传性致盲疾病，由线粒体 DNA 中的 G11778A 突变引起，该突变影响呼吸链复合物 I 的 ND4 基因。我们的小组开发了一种同素异体表达的方法，该方法引入该线粒体基因的“核版本”，然后使用线粒体靶向序列将细胞质合成的蛋白质靶向线粒体。生物统计中心的作用将是在试验程序的开发和实施、数据输入和报告生成方面支持该试验；确认参与者的资格标准；确保数据安全；并与数据和安全监测委员会联络。