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: 9254556
• 负责人: William Jack Feuer
• 金额: $ 11.61万
• 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/9254556
• 关键词: Acute; Adverse event; Affect; Antibody titer measurement; Bilateral; Biometry; Blindness; Blood; Chronic; Clinical Trials Data Monitoring Committees; Computers; Consent Forms; Contralateral; Data; Data Security; Development; Disease; Dose; Electrocardiogram; Eligibility Determination; Enrollment; Ensure; Exclusion Criteria; Eye; Eye diseases; Gene therapy trial; Generations; Genes; Goals; Human; Human Resources; Inherited; Injectable; 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; Molecular; Monitor; Mutate; Mutation; NADH dehydrogenase (ubiquinone); Nuclear; Outcome; Participant; Patient Recruitments; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Postoperative Period; Procedures; Proteins; Protocols documentation; Recruitment Activity; Reporting; Respiratory Chain; Role; Safety; Sample Size; Schedule; Secure; System; Testing; Therapy trial; Time; Toxic effect; Universities; Vision; Visit; Visual Acuity; Visual Fields; adeno-associated viral vector; 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; trial design; 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在I期临床试验中为AAV介导的人ND4基因的递送的安全性提供生物统计学和数据管理支持，该试验是对突变的G11778A mtDNA患者的临床试验，然后转化为II期研究以在此计划的后来的几年中证明有效性。第一阶段将由一项开放标签，单方面的，单剂量的单剂量玻璃体玻璃体经室注射在剂量降低的研究中，每名患者的AAV-ND4在调查三个矢量剂量的安全性（5x10E9 VG，2.46x10E10 VG和1x10E11 vg）中的安全性少量（5x10E9 VG，2.46x10E11 vg和1x10e11 vg）。慢性双边，严重的视觉损失超过1年（AIM 1）或急性双侧视觉损失少于1年（AIM 2），最后，在眼睛的视线中，我们知道从视觉损失开始后6个月内就已经预定了很大的视力（AIM 3）。 Leber的遗传性视神经病变（LHON）的生物统计学中心（BC）：基因治疗临床试验将与John Guy博士合作实施这一第一阶段临床试验。 LHON是一种由线粒体DNA中G11778A突变引起的母体遗传性盲疾病，影响了呼吸链复合物I的ND4基因。我们的小组已经开发了一种用于同类表达的方法，该方法是引入该线粒体基因的“核版本”的程序，然后以线粒体靶向序列靶向细胞质合成的蛋白。生物统计学中心的作用将是支持该三角法规，以开发和实施试验程序，数据输入和报告生成；确认参与者的资格标准；确保数据安全；并与HE数据和安全监测委员会联系。