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

Leber遗传性视神经病变(LHON)生物统计中心：基因治疗 临床试验将继续与John Guy博士合作，升级到更高剂量的 AAV-ND4基因治疗研究产品(IP)在这一阶段的临床试验中。LHON是一个 母系遗传性线粒体DNA盲病(ND4基因G11778A突变 基因)。盖伊博士开发了一种异体表达的方法，这是一种 引入这种线粒体基因的“核版本”，然后以细胞质为靶点 通过线粒体靶向序列将合成的蛋白质结合到线粒体。LHON 基因治疗临床试验是评估开放标签的安全性的第一阶段临床试验， 单侧玻璃体内注射腺相关病毒载体(AAV-ND4)LHON 病人。卑诗省为这项研究提供生物统计和协调中心的支持。 不列颠哥伦比亚大学的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，并与盖伊博士就未来资助的自然病史进行合作 对LHON家族队列的研究，包括受影响的患者和携带者。在 在这个I期剂量递增试验的前一个资金周期中，BC在 启动试验并确保对19名患者进行合规登记和注射后随访， 其中18例证实了小剂量和中剂量AAV-ND4腹腔注射的安全性。它也是 负责数据质量、管理和进入21 CRF Part 11合规性 数据库。这一努力导致在同行评议的眼科杂志上发表了两篇报告 文学。 研究小组现在建议采用其开发、实施和验证的程序 对于低剂量和中剂量，升级到较高剂量

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