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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