权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mito-Targeted AAV to treat Leber Hereditary Optic Neuropathy caused by ND4 mutations

Mito 靶向 AAV 治疗 ND4 突变引起的 Leber 遗传性视神经病

基本信息

批准号：
10331798
负责人：
Byron L Lam
金额：
$ 106.13万
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：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331798
关键词：
ATP Synthesis Pathway Acute Adverse effects Affect Amino Acids Animal Model Apoptosis Arginine Atrophic Axon Bilateral Biological Birth Blindness Capsid Categories Cell model Cells Characteristics Chronic Clinical Clinical Trials Clinical Trials Design Codon Nucleotides Complex Cytochrome c Reductase DNA DNA Maintenance DNA biosynthesis DNA delivery Data Dependovirus Development Disease Effectiveness FDA approved Family Family member Funding Future Gene Delivery Gene Transfer Generations Genes Genetic Code Glaucoma Goals Histidine Histopathology Human Human Characteristics Infrastructure Injections Investigational Drugs Investigational New Drug Application Lead Leber&apos s Hereditary Optic Neuropathy Leber&apos s amaurosis Macaca mulatta Microinjections Mitochondria Mitochondrial DNA Mitochondrial Diseases Modeling Monoclonal Antibody R24 Mus Mutate Mutation NADH dehydrogenase (ubiquinone)Natural History Neurodegenerative Disorders Nuclear Optic Disk Optic Nerve Organelles Oxidative Phosphorylation Pathogenesis Patients Phase I Clinical Trials Phase I/II Clinical Trial Phase I/II Trial Phenotype Preclinical Testing Primates Rare Diseases Reactive Oxygen Species Regulatory Element Research Research Personnel Respiration Respiratory Chain Respiratory physiology Rest Retina Retinal Diseases Rodent Safety Series Site-Directed Mutagenesis Structure Swelling Technology Testing Time Tissues Toxicology Transgenic Mice Transgenic Organisms Translational Research Treatment Efficacy United States National Institutes of Health Viral Visual system structure Work adeno-associated viral vector antibody test blastocyst clinically relevant design effective therapy efficacy testing experience ganglion cell gene therapy in vivo intravitreal injection meetings mouse model multidisciplinary mutant nonhuman primate optic nerve disorder preclinical safety prevent promoter prospective retinal ganglion cell degeneration safety study safety testing sight restoration translational study vector vector biodistribution visual optics

项目摘要

Research Summary Mutations in mitochondrial DNA (mtDNA) lead to a spectrum of neurodegenerative diseases for which no effective treatment exists. The most common of these is Leber hereditary optic neuropathy (LHON) caused by mutations in NADH dehydrogenase subunit genes (ND1, ND4 or ND6), which is complex I of the respiratory chain. Therapies for LHON in common with all disorders caused by mutated mtDNA are inadequate, in large part because of the barrier in delivering DNA into the organelle. We have successfully broken through this barrier by developing a pioneering adeno-associated virus (AAV) vector to which a mitochondrial targeting sequence (MTS) was appended to the viral capsid. The modified vector delivered the ND4 gene directly to the mitochondria for reversal of visual loss in mice with mutated G11778A ND4 responsible for more than half of all LHON cases, the rest caused by mutated ND1 and ND6. We will now design, modify and test the efficacy and safety of a clinically relevant vector for treatment of this mitochondrial disease by delivery of genes encoding the promoter and regulatory elements of a normal mitochondrially encoded human ND4 subunit to affected cells and tissues for rescue of cultured human LHON cells harboring the NADH dehydrogenase subunit 4 mutation causing LHON and then transgenic mice and primates with mutated ND4. The ND4 mouse we developed by injection of a MTS AAV containing mutated G11778A ND4 into the rodent blastocyst has visual loss progressing to blindness a year after birth, optic nerve head swelling followed by atrophy and degeneration of retinal ganglion cells, which are the characteristic hallmarks of LHON patients. Our goals are: (A) To facilitate translational studies for LHON by developing a clinical grade MTS AAV vector that accommodates the wild-type ND4 LHON gene and regulatory elements in a single AAV cassette. (B) To test expression to rescue respiration in cybrid cells and the visual system of mice and primates with mutated G11778A ND4. (C) To evaluate biological effects of intravitreal delivery of MTS AAV vectors in normal rodents and primates that result in mitochondrial gene transfer without adverse effects. (D) To develop an IND application for a single AAV containing normal ND4 for a future phase I/II clinical trial designed to restore the vision of patients with the commonest and most severe LHON mutation and prevent visual loss in their family members in a U10 application to follow successful completion of this R24.

研究综述线粒体DNA（mtDNA）突变导致一系列神经退行性疾病，有有效的治疗方法。其中最常见的是Leber遗传性视神经病变（LHON）， NADH脱氢酶亚基基因（ND 1、ND 4或ND 6）突变，其是呼吸系统的复合物I，链LHON的治疗与所有由突变的mtDNA引起的疾病一样是不够的，部分原因是将DNA运送到细胞器中的障碍。我们已经成功地突破了这一点通过开发一种开创性的腺相关病毒（AAV）载体，序列（MTS）附加到病毒衣壳。经修饰的载体将ND 4基因直接递送至线粒体用于逆转具有突变的G11778 A ND 4的小鼠的视力丧失， LHON病例，其余由突变的ND 1和ND 6引起。我们现在将设计，修改和测试功效，用于通过递送编码线粒体疾病的基因治疗该线粒体疾病的临床相关载体的安全性 - 正常的经尿道编码的人ND 4亚基的启动子和调节元件，用于拯救具有NADH脱氢酶亚基4突变的培养的人LHON细胞的组织导致LHON，然后导致ND 4突变的转基因小鼠和灵长类动物。我们开发的ND 4小鼠将含有突变的G11778 A ND 4的MTS AAV注射到啮齿动物胚泡中，至出生后一年失明，视神经乳头肿胀，继而视网膜萎缩变性，神经节细胞，这是LHON患者的特征性标志。我们的目标是：（A）促进通过开发容纳野生型LHON的临床级MTS AAV载体进行LHON的翻译研究 ND 4 LHON基因和调控元件在单个AAV盒中。(B)测试表情以拯救呼吸在胞质杂交细胞和视觉系统的小鼠和灵长类动物与突变的G11778 A ND 4。(C)评价玻璃体内递送MTS AAV载体在正常啮齿动物和灵长类动物中的生物学效应，线粒体基因转移无副作用。(D)为单个AAV开发IND申请含有正常ND 4的用于未来I/II期临床试验，旨在恢复患有最常见和最严重的LHON突变，并防止其家庭成员的视力丧失，成功完成此R24后的申请。