Intravenous MitoTargeted AAV9 Gene Therapy for Treatment of Visual Loss and Encephalopathy in Leigh Syndrome and NARP

静脉注射 Mito 靶向 AAV9 基因疗法治疗 Leigh 综合征和 NARP 患者的视力丧失和脑病

基本信息

批准号：
9893880
负责人：
Hong Yu
金额：
$ 38.38万
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：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893880
关键词：
Adult Adverse effects Affect Alleles American Animals Ataxia Autopsy Biological Birth Blindness Blood - brain barrier anatomy Capsid Proteins Categories Cells Cessation of life Child Clinical Clinical Trials DNA DNA delivery Development Disease Electroretinography Encephalopathies Epitopes Evaluation Eye Gene Delivery Gene Transfer Genes Genetic Code Goals Heart Homologous Gene Human Infant Inherited Injections Intravenous Knowledge Laser Scanning Confocal Microscopy Lead Leber&apos s Hereditary Optic Neuropathy Leigh Disease Link Mitochondria Mitochondrial DNA Mitochondrial Diseases Molecular Mus Mutate Mutation Nervous System Physiology Nervous system structure Neuro-Ocular System Neurodegenerative Disorders Neurologic Nucleotides Open Reading Frames Optic Atrophy Optic Nerve Organelles Oxidative Phosphorylation Paralysed Pathogenesis Patients Pattern Phase Phase I/II Clinical Trial Proteins Rare Diseases Respiration Retinitis Pigmentosa Rodent Rotarod Performance Test Safety Serotyping Technology Testing Toxic effect Transgenic Mice Transgenic Organisms Treatment Efficacy Veins Vertebral column Virion Virus Vision Wild Type Mouse Work adeno-associated viral vector blastocyst clinically relevant design early childhood effective therapy efficacy testing emerging adult encephalomyelopathy gene therapy human disease intravenous injection mutant nervous system disorder new technology non-invasive imaging oligomycin sensitivity-conferring protein optic nerve disorder premature prevent promoter transgene expression translational study vector zygote

项目摘要

Mutations in mitochondrial DNA lead to a spectrum of neurodegenerative diseases for which no effective treatment exists. This is a group of untreatable disorders affecting the eye, nervous system and heart, some clinically characterized over a century ago, but they are now known to be a spectrum of molecularly defined diseases. We had chosen to start with one of the most severe, the ATP6 mutation (T8993G) in mitochondrial (mt) DNA responsible for Maternally Inherited Leigh Syndrome (MILS), a neurologic disease renowned for causing blindness and rapidly fatal encephalomyelopathy in early childhood or Neurogenic Ataxia and Retinitis Pigmentosa in early adulthood. We have made major strides towards determining the pathogenesis and testing treatments for another common mitochondrial disorder Leber hereditary optic neuropathy (LHON). In this application, we propose to design, modify and test the efficacy and safety of a clinically relevant vector for the treatment of MILS and NARP caused by mutated ATP6. Our Aims are: (1) To facilitate translational studies for MILS and NARP by developing an MTS AAV serotype 9 vector for intravenous use to deliver the normal ATP6 gene directly to the mitochondria and test expression to rescue respiration in cybrid cells with 100% mutated T8993G mitochondrial DNA. (2) To evaluate biological effects of intravenous delivery of MTS AAV9 vectors in normal mice that result in mitochondrial gene transfer without adverse effects.(3) To rescue visual loss, encephalomyelopathy and death in transgenic ATP6 mice. We hope to identify the conditions for long-term rescue of visual loss and encephalomyelopathy in mice, so that this approach can be tested in a phase I/II clinical designed to restore visual and neurologic function in MILS and NARP patients.

线粒体 DNA 突变会导致一系列神经退行性疾病，而这些疾病目前尚无定论。这是一组影响眼睛、神经的无法治疗的疾病。系统和心脏，其中一些在一个多世纪前就有了临床特征，但现在已知它们我们选择从分子定义最广泛的疾病之一开始。严重的是，线粒体 (mt) DNA 中的 ATP6 突变 (T8993G) 导致母体遗传性利氏综合症 (MILS)，一种因导致失明和失明而闻名的神经系统疾病儿童早期迅速致命的脑脊髓病或神经源性共济失调和视网膜炎成年早期的色素性。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另一种常见的线粒体疾病是莱伯遗传性视神经病（LHON）。应用程序中，我们建议设计、修改和测试临床相关的功效和安全性用于治疗由突变的 ATP6 引起的 MILS 和 NARP 的载体我们的目标是：（1）通过开发 MTS AAV 血清型 9 载体促进 MILS 和 NARP 的转化研究用于静脉注射，将正常的 ATP6 基因直接递送至线粒体并进行测试表达以挽救具有 100% 突变 T8993G 线粒体 DNA 的 cybrid 细胞的呼吸。 (2) 评价MTS AAV9载体在正常小鼠中静脉注射的生物学效应导致线粒体基因转移而没有副作用。(3) 为了挽救视力丧失，我们希望确定转基因 ATP6 小鼠的脑脊髓病和死亡的情况。用于长期挽救小鼠视力丧失和脑脊髓病，因此该方法可以在旨在恢复 MILS 视觉和神经功能的 I/II 期临床中进行测试 NARP 患者。