Giant Axonal Neuropathy Gene Therapy

巨大轴突神经病基因治疗

• 批准号: 8674153
• 负责人: Steven J Gray
• 金额: $ 32.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8674153
• 关键词: Affect; Afferent Neurons; Amyotrophic Lateral Sclerosis; Astrocytes; Ataxia; Axon; Axonal Neuropathy; Behavioral; Biodistribution; Biological Assay; Biological Markers; Biological Preservation; Brain; Cerebrospinal Fluid; Cessation of life; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Diffusion Magnetic Resonance Imaging; Diffusion weighted imaging; Disease; Dose; Foundations; Functional disorder; Funding; Ganglia; Gene Transfer; Genes; Glial Fibrillary Acidic Protein; Goals; Human; Individual; Inherited; Injection of therapeutic agent; Intermediate Filaments; Intrathecal Injections; Investigational Drugs; Knock-out; Life; Magnetic Resonance Imaging; Methods; Microtubules; Modeling; Motor Neurons; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Online Mendelian Inheritance In Man; Organ; Outcome Measure; Pathology; Patients; Peripheral; Phase; Phase I Clinical Trials; Phase II/III Trial; Phenotype; Proteins; Rattus; Route; Safety; Sampling; Schwann Cells; Spinal Cord; Spinal Muscular Atrophy; Spinal Puncture; Symptoms; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; United States National Institutes of Health; Vimentin; Visceral; alpha-internexin; autonomic nerve; cognitive function; gene therapy; gene therapy clinical trial; gigaxonin; human disease; improved; loss of function mutation; meetings; nervous system disorder; neurofilament; new therapeutic target; nonhuman primate; older patient; patient population; peripherin; preclinical study; public health relevance; therapeutic target; vector

TITLE: Giant Axonal Neuropathy Gene Therapy ABSTRACT Giant Axonal Neuropathy (GAN, OMIM #256850) is a rare chronic neurodegenerative disease characterized by enlarged axons with disordered microtubules and intermediate filaments (IFs), which is fatal by the third decade of life. The disease pathology is due to homozygous loss-of- function mutations in the GAN gene, which encodes the protein gigaxonin. The underlying pathology is due to the disorganization and accumulation of IFs, including vimentin, alpha- internexin, neurofilaments, peripherin, and GFAP. GAN patients have normal cognitive function, and the most severe (and fatal) symptoms of GAN are the result of dysfunction and death of motor and sensory neurons in the spinal cord and DRG. The phenotypic contribution of IF dysfunction in other tissues such as the brain, autonomic nerves, and peripheral organs is poorly understood. Since 2008 we have been developing a gene transfer approach to treat GAN using intrathecal delivery of AAV9/GAN vectors, funded entirely by a small non-profit foundation called Hannah's Hope Fund. This effort culminated in a preIND (investigational new drug) meeting with the FDA in January 2012, and a RAC meeting for a proposed clinical trial in June 2013. Submission of an IND for a Phase I safety GAN gene therapy clinical trial is expected in summer of 2013, focused on rescuing spinal cord motor and sensory neurons. Sponsored by Hannah's Hope Fund, this trial will occur at the NIH Clinical Center under the direction of Dr. Carsten Bonnemann. This Phase I trial is aimed at establishing the safety of our general gigaxonin gene transfer approach in older patients that are eager to participate and otherwise untreatable. This patient population is made up of individuals that will be dead or too far progressed in their disease to participate in a later trial. While the Phase I trial is underway, this proposal aims to better characterize GAN in ways that could inform a Phase II/III trial and also identify new therapeutic targets if our approach needs to be modified. Further, it aims to optimize the gene transfer approach and develop a GAN knock-out rat.

标题：巨轴突神经病基因治疗 摘要 巨轴突神经病（GAN，OMIM #256850）是一种罕见的慢性神经退行性疾病 其特征在于具有无序微管和中间丝（IF）的扩大的轴突， 这是致命的第三个十年的生活。疾病病理是由于纯合性缺失- GAN基因的功能突变，该基因编码蛋白gigaxonin。底层 病理学是由于IF，包括波形蛋白，α- 连接蛋白、神经丝、外周蛋白和GFAP。GAN患者具有正常的认知功能， GAN最严重（和致命）的症状是功能障碍和死亡的结果， 脊髓和DRG中的运动和感觉神经元。IF的表型贡献 其他组织如脑、自主神经和外周器官的功能障碍， 不太了解。自2008年以来，我们一直在开发一种基因转移方法来治疗 GAN使用鞘内递送AAV 9/GAN载体，完全由小型非营利组织资助 一个名为汉娜希望基金的基金会。这一努力最终导致了一个preIND（研究性新 2012年1月与FDA举行的药物）会议，以及2012年1月与RAC举行的拟议临床试验会议。 2013年6月。提交I期安全性GAN基因治疗临床试验的IND 预计在2013年夏天，重点是拯救脊髓运动和感觉神经元。 由汉娜希望基金会赞助，这项试验将在美国国立卫生研究院临床中心进行， Carsten Bonnemann博士的指导。这项I期试验旨在确定我们的 一般gigaxonin基因转移方法在老年患者渴望参与， 否则无法治愈这个病人群体是由个人，将死亡或太 他们的病情进展得很慢，参加了后来的试验。虽然第一阶段试验是 目前，该提案旨在更好地描述GAN的特征，以便为第二/第三阶段提供信息 如果我们的方法需要修改，还需要确定新的治疗靶点。此外，它 目的是优化基因转移方法，建立GAN基因敲除大鼠模型。