Leber's Hereditary Optic Neuropathy: Gene Therapy Clinical Trial

莱伯遗传性视神经病：基因治疗临床试验

• 批准号: 8828695
• 负责人: John Guy
• 金额: $ 205.04万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828695
• 关键词: ATP Synthesis Pathway; Acute; Adverse reactions; Affect; Amino Acids; Animal Model; Apoptosis; Arginine; Axon; Bilateral; Biodistribution; Blindness; Categories; Cells; Cessation of life; Child; Chronic; Clinical Trials; Codon Nucleotides; Color; Complex; Contralateral; Cultured Cells; DNA; Data; Disease; Dose; Elderly; Enrollment; Eye; Gene therapy trial; Genes; Genetic Code; Goals; Health; Heart; Histidine; Homologous Gene; Human; Individual; Injection of therapeutic agent; Lead; Leber' s Hereditary Optic Neuropathy; Letters; Maximum Tolerated Dose; Mediating; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Monitor; Mus; Mutate; Mutation; NADH dehydrogenase (ubiquinone); Natural History; Neuro-Ocular System; Nuclear; Optic Atrophy; Optic Disk; Optic Nerve; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenylalanine; Primates; Proteins; Rare Diseases; Rattus; Reactive Oxygen Species; Reading Frames; Recovery; Relative (related person); Research Personnel; Respiratory physiology; Retinal Ganglion Cells; Rodent; Rodent Model; Safety; Series; Swelling; Technology; Testing; Toxic effect; Translational Research; Tyrosine; United States National Institutes of Health; Virus; Vision; Visual Acuity; Visual Fields; Visual system structure; Work; blind; cohort; effective therapy; emerging adult; experience; gene therapy clinical trial; human disease; intravitreal injection; mouse model; multidisciplinary; mutant; next generation; nonhuman primate; novel; open label; phase 2 study; prevent; programs; research clinical testing; retinal neuron; safety testing; targeted sequencing; vector

DESCRIPTION (provided by applicant): Over the past decade, we have made major strides towards determining the pathogenesis and testing a treatment for Leber's 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 most inner retinal neurons by 1 day post injection and it integrated into Complex I. Furthermore, in rodent eyes also injected with a mutant Gl 1778A 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. Primates vitreally injected with untagge ND4 had no adverse reactions, suggesting that this vector should be a safe and effective platform for clinical testing in LHON. Our goal in this application is to test the 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 1xlOel1 vg) in a small number of patients with molecularly confirmed Gl 1778A-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 tha 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).

描述（由申请人提供）：在过去的十年中，我们在确定莱伯遗传性视神经病（LHON）的发病机制和测试治疗方法方面取得了重大进展。我们成功地在核遗传密码中表达了复合物 I 的野生型人 NADH 泛醌氧化还原酶亚基 4 (ND4)。该蛋白质通过线粒体靶向序列导入线粒体。该基因被包装到下一代酪氨酸至苯丙氨酸修饰的自互补腺相关病毒（AAV）中，然后注射到啮齿动物的眼睛中。注射后 1 天，在大多数视网膜内神经元中快速检测到带有 FLAG 标记的野生型人 ND4，并将其整合到复合物 I 中。此外，在啮齿动物眼睛中还注射了导致大多数 LHON 病例的突变型 GL 1778A ND4 同源物，野生型 ND4 恢复了有缺陷的 ATP 合成，抑制了视力丧失，减少了视网膜神经节细胞的凋亡，并防止了视网膜神经节细胞的死亡。 视神经中长期存在的轴突。以相关滴度注射到离体人眼中的自我互补野生型 ND4 在大多数视网膜神经节细胞中表达，表明它在我们的 LHON 患者中也会如此。灵长类动物玻璃体注射未标记的ND4没有不良反应，表明该载体应该是LHON临床测试的安全有效的平台。我们本申请的目标是在 G11778A mtDNA 突变患者的 I 期临床试验中测试 AAV 介导的人类 ND4 基因传递的安全性，然后进入 II 期研究以证明该项目后期的有效性。第一阶段将包括在一项剂量递增研究中，对每名患者的病情较差的眼睛进行开放标签、单侧、单剂量玻璃体内注射 AAV-ND4，该研究调查三种载体剂量（5x10e9 vg、2.46x10e10 vg 和 1x10el1 vg）在少数具有分子证实的 GL 1778A 突变线粒体 DNA 的慢性病患者中的安全性。 双侧严重视力丧失超过 1 年（目标 1）或急性双侧数次视力丧失少于 1 年（目标 2），最后是视力较好但我们知道在第一只眼睛开始视力丧失后 6 个月内注定会丧失显着视力的眼睛（目标 3）。