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.

我们已经在确定发病机理和测试治疗方面取得了长足的进步 Leber世袭神经病（LHON）。我们成功地表达了野生型人类核遗传密码中复合物I的NADH泛酮氧化还原酶亚基4（ND4）。这通过线粒体靶向序列的代理将蛋白质进口到线粒体中。将基因包装到下一代酪氨酸中然后注入啮齿动物的眼睛。旗标记的野生型人ND4 注射后1周，在90％的视网膜神经节细胞中迅速检测到进一步。负责大多数LHON的情况，野生型ND4恢复了有缺陷的ATP合成，抑制视觉丧失，减少视网膜神经节细胞的凋亡，并阻止长期持续存在的视神经中的轴突。注入自我平衡的野生型ND4 在大多数视网膜神经节细胞中表达的离体人眼中的相关滴度，表明它将在我们的LHON患者中这样做。与Leber先天性amaurosis（RPE65突变）不同，没有FDA批准的LHON视觉损失的治疗方法。在过去的四年中，我们有在ND4亚基中招募了19例LHON患者G11778A突变的遗传证实旨在测试基因治疗载体安全性的I阶段I临床试验的复杂I （IND＃15941）。 9例患者被玻璃体注射低剂量的自我平衡SCAAV2-- P1ND4V2，9次注射中剂量，并注射高剂量。我们的目标竞争的更新应用是测试较高剂量AAV的安全性和耐受性突变患者的I期临床试验中介导的人ND4基因的递送 G11778a mtDNA为了在该计划的后期证明有效性。