Biostatistics Center for Lebers Hereditary Optic Neuropathy (LHON): Gene Therapy Clinical Trial

Lebers 遗传性视神经病 (LHON) 生物统计中心：基因治疗临床试验

• 批准号: 10408740
• 负责人: Robert Charles O'Brien
• 金额: --
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408740
• 关键词: ATP Synthesis Pathway; Acute; Adverse effects; Affect; Amino Acids; Animal Model; Apoptosis; Arginine; Axon; Bilateral; Biodistribution; Biometry; Blindness; Blood; Cells; Chemistry; Childhood; Chronic; Clinical Trials; Clinical Trials Design; Codon Nucleotides; Collaborations; Complex; Contralateral; Cultured Cells; DNA; Data; Databases; Disease; Dose; Drug usage; Enrollment; Ensure; Eye; Eye diseases; FDA approved; Family; Funding; Gene Transduction Agent; Genes; Genetic; Genetic Code; Goals; Heart; Histidine; Homologous Gene; Human; Inherited; Injections; Investigation; Investigational Therapies; Lead; Leber' s Hereditary Optic Neuropathy; Leber' s amaurosis; Leber' s disease; Legal Blindness; Letters; Literature; Measures; Mediating; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Molecular; Monitor; Mus; Mutate; Mutation; NADH dehydrogenase (ubiquinone); Natural History; Neuro-Ocular System; Neurologic; Nuclear; Ophthalmology; Optic Disk; Optic Nerve; Oxidative Phosphorylation; Pathogenesis; Patients; Pattern; Peer Review; Phase; Phase I Clinical Trials; Play; Procedures; Proteins; Publications; RPE65 protein; Rattus; Reactive Oxygen Species; Reading Frames; Recovery; Reporting; Research Personnel; Respiratory physiology; Retina; Retinal Ganglion Cells; Role; Safety; Series; Serum; Swelling; Technology; Testing; Toxic effect; United States National Institutes of Health; Viral Vector; Visual Acuity; Visual Fields; Visual system structure; Work; body system; cohort; data quality; effective therapy; emerging adult; experience; follow-up; ganglion cell; gene therapy; gene therapy clinical trial; intravitreal injection; mitochondrial DNA mutation; mutant; neutralizing antibody; nonhuman primate; open label; prevent; prospective; retinal apoptosis; safety testing; vector

The Biostatistics Center (BC) for Leber's Hereditary Optic Neuropathy (LHON): Gene Therapy Clinical Trial will continue its collaboration with Dr. John Guy, escalating to higher doses of the AAV-ND4 gene therapy investigational product (IP) in this Phase 1 clinical trial. LHON is a maternally inherited blinding disease of mitochondrial DNA (G11778A mutation in the ND4 gene). Dr. Guy has developed a method for allotopic expression, which is a procedure to introduce a “nuclear version” of this mitochondrial gene and to then target the cytoplasmically synthesized protein to the mitochondria with a mitochondrial targeting sequence. The LHON Gene Therapy Clinical Trial is a Phase 1 clinical trial to evaluate the safety of an open-label, unilateral, single-dose of intravitreal injection of adenoassociated viral vector (AAV-ND4) LHON patients. The BC provides biostatistical and coordinating center support for the study. The BC investigators are an experienced team, who have been involved with ophthalmological clinical trials since 1985 and collaborated with Dr. Guy on a prospective funded natural history study of a cohort of LHON families, which included affected patients and carriers. In the previous funding cycle of this Phase I dose escalation trial, the BC played a critical role in initiating the trial and ensuring compliant enrollment and post injection follow up of 19 patients, 18 of which demonstrated safety of the low and medium dose AAV-ND4 IP. It is also responsible for data quality, management, and entry into the 21 CRF part 11 compliant database. This effort led to the publication of two reports in the peer-reviewed ophthalmology literature. The study team now proposes to employ its procedures, developed, implemented, and proven for the low and medium doses, to escalation of higher doses

莱伯遗传性视神经病 (LHON) 生物统计中心 (BC)：基因治疗 临床试验将继续与 John Guy 博士合作，逐步升级至更高剂量 该 1 期临床试验中的 AAV-ND4 基因治疗研究产品 (IP)。 LHON 是一个 母系遗传性线粒体 DNA 致盲病（ND4 基因组中的 G11778A 突变） 基因）。 Guy 博士开发了一种同位素表达方法，该方法 引入该线粒体基因的“核版本”，然后靶向细胞质 通过线粒体靶向序列合成蛋白质到线粒体。莱恩 基因治疗临床试验是一项一期临床试验，旨在评估开放标签、 单侧、单剂量玻璃体内注射腺相关病毒载体 (AAV-ND4) LHON 患者。 BC 为该研究提供生物统计和协调中心支持。 BC调查员是一支经验丰富的团队，他们曾参与过眼科研究 自 1985 年以来一直进行临床试验，并与 Guy 博士合作开展一项前瞻性资助的自然历史研究 对 LHON 家族队列的研究，其中包括受影响的患者和携带者。在 在这一 I 期剂量递增试验的先前资助周期中，BC 发挥了关键作用 启动试验并确保 19 名患者的合规入组和注射后随访， 其中 18 项证明了低剂量和中剂量 AAV-ND4 IP 的安全性。这也是 负责数据质量、管理并符合 21 CRF 第 11 部分 数据库。这项努力导致在同行评审的眼科杂志上发表了两份报告 文学。 研究小组现在建议采用其开发、实施和证明的程序 对于低剂量和中等剂量，逐渐增加更高剂量

项目成果

The Tube Versus Trabeculectomy IRIS® Registry Study: Cohort Selection and Follow-up and Comparisons to the Randomized Controlled Trial.

管与小梁切除术 IRIS® 注册研究：队列选择和随访以及与随机对照试验的比较。

• DOI: 10.1016/j.ajo.2020.11.014
• 发表时间: 2021
• 期刊: American journal of ophthalmology
• 影响因子: 4.2
• 作者: Vanner,ElizabethA;Sun,CatherineQ;McSoley,MatthewJ;Persad,PatriceJ;Feuer,WilliamJ;Lum,Flora;Kelly,ScottP;Parrish,RichardK;Chang,TaC;Gedde,StevenJ
• 通讯作者: Gedde,StevenJ