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

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学和数据管理支持，用于在G11778 A mtDNA突变患者的I期临床试验中测试AAV介导的人ND 4基因递送的安全性，然后进入II期研究，以证明该项目后期的疗效。I期将包括在剂量递增研究中，在每名患者的较差眼中开放标签、单侧、单剂量玻璃体内注射AAV-ND 4，研究三种载体剂量的安全性。（5x 10 e9 vg，2.46x10e10 vg和1x 10 e11 vg）在少数患有慢性双侧，严重视力丧失超过1年（目标1）或急性双侧几个视力丧失不到1年（目标2），然后，最后，在视力较好的眼睛，但我们知道是注定要失去显着的视力在6个月内从第一只眼睛视力丧失发作（目标3）。Leber遗传性视神经病变（LHON）生物统计学中心（BC）：基因治疗临床试验将与John Guy博士合作实施这项第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G11778 A突变引起，该突变影响呼吸链复合体I的ND 4基因。我们的小组已经开发了一种用于同素异形表达的方法，该方法是引入该线粒体基因的“核版本”，然后用线粒体靶向序列将胞质合成的蛋白质靶向到线粒体中的过程。生物统计中心的作用是在试验程序的制定和实施、数据录入和报告生成方面支持本试验;确认受试者的合格标准;确保数据安全性;并与数据和安全性监查委员会联络。

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.