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：
9218874
负责人：
John Guy
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9218874
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 Development Disease Electroretinography Encephalopathies Epitopes Evaluation Eye Gene Delivery Gene Transfer Genes Genetic Code Goals Heart Homologous Gene Human Infant Inherited Injectable Injection of therapeutic agent 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 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中的突变导致一系列神经退行性疾病的频谱存在有效的治疗。这是一群影响眼睛的不可治疗的疾病，紧张系统和心脏，有些在一个多世纪前临床表征，但现在已知它们成为分子定义的疾病的范围。我们选择从最重要的严重的线粒体（MT）DNA中的ATP6突变（T8993G）负责母体遗传性利综合症（MILS），一种因引起失明和闻名的神经系统疾病幼儿期或神经性共济失调和视网膜炎的快速致命性脑瘤病成年早期的色素。我们已经朝着确定发病机理和测试治疗方面取得了长足的进步另一种常见的线粒体障碍列伯遗传神经病变（LHON）。在这个应用，我们建议设计，修改和测试临床相关的效率和安全性由突变ATP6引起的MILS和NARP处理的载体。我们的目标是：（1）通过开发MTS AAV血清型9矢量来促进MILS和NARP的转化研究用于静脉用途，将正常的ATP6基因直接传递到线粒体并进行测试用100％突变的T8993G线粒体DNA挽救胞质细胞中呼吸的表达。（2）评估正常小鼠静脉输送MTS AAV9载体的生物学作用这导致线粒体基因转移而没有不利影响。（3）为了挽救视觉丧失，转基因ATP6小鼠的脑瘤病和死亡。我们希望确定条件为了长期营救小鼠的视觉丧失和脑膜病，以便这种方法可以在I/II期临床设计中进行测试，以恢复MILS和 NARP患者。