Lebers Hereditary Optic Neuropathy: Gene Therapy

莱伯斯遗传性视神经病：基因治疗

基本信息

批准号：
9921407
负责人：
Byron L Lam
金额：
--
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/9921407
关键词：
ATP Synthesis Pathway Acute Adverse effects Affect Amino Acids Animal Model Apoptosis Arginine Axon Bilateral Biodistribution Blindness Blood Categories Cells Chemistry Childhood Chronic Clinical Clinical Trials Clinical Trials Design Codon Nucleotides Complex Contralateral Cultured Cells DNA Data Disease Dose Drug usage Enrollment Eye FDA approved Family Funding Gene Transduction Agent Genes Genetic Genetic Code Glaucoma Goals Heart Histidine Homologous Gene Human Infrastructure Injections Leber&apos s Hereditary Optic Neuropathy Leber&apos s amaurosis Leber&apos s disease Legal Blindness Letters Measures Mediating Mitochondria Mitochondrial DNA Mitochondrial Diseases Molecular Monitor Mus Mutate Mutation NADH dehydrogenase (ubiquinone)Neuro-Ocular System Neurologic Nuclear Optic Disk Optic Nerve Oxidative Phosphorylation Pathogenesis Patients Pattern Phase Phase I Clinical Trials Phenylalanine Proteins RPE65 protein Rare Diseases Rattus Reactive Oxygen Species Reading Frames Recovery Research Personnel Respiratory physiology Retina Retinal Diseases Retinal Ganglion Cells Rodent Safety Series Serum Swelling Technology Testing Toxic effect Translational Research Tyrosine United States National Institutes of Health Virus Visual Acuity Visual Fields Visual system structure Work effective therapy emerging adult experience ganglion cell gene therapy human disease intravitreal injection multidisciplinary mutant neutralizing antibody next generation nonhuman primate open label prevent programs retinal apoptosis safety testing vector

项目摘要

We have made major strides towards determining the pathogenesis and testing a treatment for Leber Hereditary Optic Neuropathy (LHON). We successfully expressed the wild-type human NADH ubiquinone oxidoreductase subunit 4 (ND4) of complex I in the nuclear genetic code. The protein was imported into the mitochondria by agency of a mitochondrial targeting sequence. The gene was packaged into next generation tyrosine to phenylalanine modified self-complementary adenoassociated virus (AAV) then injected into rodent eyes. FLAG-tagged wild-type human ND4 was detected quickly in 90% of retinal ganglion cells by 1 week post injection and it integrated into Complex I. Furthermore, in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON, wild-type ND4 restored defective ATP synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells and prevented demise of axons in the optic nerve that persisted long-term. The self-complementary wild-type ND4 injected at the relevant titer into the ex vivo human eye expressed in most retinal ganglion cells, suggesting that it will do so in our LHON patients. Unlike Leber Congenital Amaurosis (RPE65 mutation), there is no FDA approved treatment for the visual loss of LHON. Over the past 4 years we have enrolled 19 LHON patients with genetic confirmation of the G11778A mutation in the ND4 subunit of complex I into a phase I clinical trial designed to test the safety of our gene therapy vector (IND# 15941). Nine patients were vitreally injected with low dose self-complementary scAAV2- P1ND4v2, nine injected with medium doses and one injected with high dose. Our goal in this competing renewal application is to test the safety and tolerability of higher doses of AAV mediated delivery of the human ND4 gene in our phase I clinical trial of patients with mutated G11778A mtDNA in order to move to prove efficacy in the later years of this program.

我们在确定发病机制和测试治疗方法方面取得了重大进展莱伯遗传性视神经病（LHON）。我们成功表达了野生型人类核遗传密码中复合物 I 的 NADH 泛醌氧化还原酶亚基 4 (ND4)。这蛋白质通过线粒体靶向序列导入线粒体。这基因被包装成下一代酪氨酸至苯丙氨酸修饰的自互补体然后将腺相关病毒（AAV）注射到啮齿动物的眼睛中。 FLAG 标记的野生型人 ND4 注射后 1 周，在 90% 的视网膜神经节细胞中快速检测到，并整合此外，在啮齿动物眼睛中还注射了突变体 G11778A ND4 同源物导致大多数 LHON 病例的原因是野生型 ND4 恢复了有缺陷的 ATP 合成，抑制视力丧失，减少视网膜神经节细胞的凋亡并防止细胞死亡视神经中长期存在的轴突。注射的自我互补野生型ND4 以相关滴度进入离体人眼并在大多数视网膜神经节细胞中表达，表明它会在我们的 LHON 患者中发挥作用。与莱伯先天性黑蒙（RPE65 突变）不同，目前尚无 FDA 批准的治疗 LHON 视力丧失的方法。在过去的 4 年里，我们入组了 19 名 LHON 患者，这些患者的 ND4 亚基中存在 G11778A 突变的基因确认复合物 I 进入 I 期临床试验，旨在测试我们的基因治疗载体的安全性（IND#15941）。九名患者接受了玻璃体注射低剂量自我补充的 scAAV2- P1ND4v2，9 只注射中等剂量，1 只注射高剂量。我们在这方面的目标竞争性更新申请是为了测试更高剂量AAV的安全性和耐受性在我们针对突变患者的 I 期临床试验中介导人类 ND4 基因的传递 G11778A mtDNA 是为了在该计划的后期证明其功效。