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

• 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
• 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' 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

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突变导致一系列神经退行性疾病， 这是一组无法治疗的疾病，影响眼睛，神经， 系统和心脏，其中一些在一个世纪前就已具有临床特征，但现在已知它们 是一系列分子定义的疾病。我们选择了一个 严重的是，线粒体（mt）DNA中的ATP 6突变（T8993 G）导致母系 遗传性利综合征（MILS），一种以导致失明而闻名的神经系统疾病， 儿童早期快速致死性脑脊髓病或神经源性共济失调和视网膜炎 成年早期的色素沉着症。 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Leber遗传性视神经病变（LHON）。在这 应用，我们建议设计，修改和测试临床相关的有效性和安全性， 用于治疗由突变的ATP 6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的翻译研究 用于静脉内使用，以将正常的ATP 6基因直接递送到线粒体， 在具有100%突变的T8993 G线粒体DNA的胞质杂种细胞中， (2)评价MTS AAV 9载体静脉给药在正常小鼠中的生物学效应 导致线粒体基因转移而没有副作用。(3)为了挽救失明， 脑脊髓病和死亡。我们希望能找出 用于长期挽救小鼠的视力丧失和脑脊髓病，因此这种方法可以 在I/II期临床试验中进行测试，旨在恢复MILS的视觉和神经功能， NARP的病人