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

基本信息

批准号：
9921410
负责人：
William Jack Feuer
金额：
$ 11.87万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921410
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&apos s Hereditary Optic Neuropathy Leber&apos s amaurosis Leber&apos 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

项目摘要

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

Leber的遗传视神经神经病（LHON）的生物统计中心（BC）：基因治疗临床试验将继续与John Guy博士合作，并升级为更高剂量在这一第一阶段临床试验中，AAV-ND4基因治疗研究产品（IP）。 lhon是一个线粒体DNA的母体遗传性盲疾病（ND4中的G11778A突变基因）。盖伊博士开发了一种用于同种异体表达的方法，这是一个程序引入该线粒体基因的“核版本”，然后以细胞质为目标用线粒体靶向序列合成到线粒体的合成蛋白。 lhon 基因治疗临床试验是一项1期临床试验，可评估开放标签的安全性，单侧的单剂量玻璃体内注射腺体相关病毒载体（AAV-ND4）LHON 患者。卑诗省为研究提供了生物统计和协调的中心支持。卑诗省调查人员是一支经验丰富的团队，他们参与了眼科自1985年以来的临床试验，并与盖伊博士合作就具有潜在的基本历史研究包括受影响的患者和携带者的LHON家族的研究。在该阶段I剂量升级试验的先前资金周期，卑诗省在启动试验并确保19例患者的兼容入学和注射后随访，其中18个证明了低剂量AAV-ND4 IP的安全性。也是负责数据质量，管理和进入21 CRF第11部分符合数据数据库。这项努力导致在同行评审的眼科中发布了两份报告文学。研究小组现在提出采用其程序，开发，实施和证明的程序对于低剂量的低剂量和中等剂量的升级