Giant Axonal Neuropathy Gene Therapy

巨大轴突神经病基因治疗

• 批准号: 8827434
• 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/8827434
• 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; Disease; Dose; Foundations; Functional disorder; Funding; Ganglia; Gene Transfer; Genes; Glial Fibrillary Acidic Protein; Goals; Health; 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 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; phase I trial; preclinical study; therapeutic target; vector

DESCRIPTION (provided by applicant): 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 late 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.

描述（由申请人提供）：巨轴突神经病（GAN，OMIM #256850）是一种罕见的慢性神经退行性疾病，其特征是轴突增大，微管和中间丝 (IF) 紊乱，在生命的 30 岁左右致命。该疾病的病理原因是编码 GAN 基因的纯合性功能丧失突变，该基因编码蛋白质 gigaxonin。潜在的病理学是由于 IF 的瓦解和积累，包括波形蛋白、α-互连蛋白、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（且致命）的症状是脊髓和背根神经节中运动和感觉神经元功能障碍和死亡的结果。对于大脑、自主神经和外周器官等其他组织中 IF 功能障碍的表型贡献知之甚少。自 2008 年以来，我们一直在开发一种基因转移方法，通过鞘内递送 AAV9/GAN 载体来治疗 GAN，该方法完全由一个名为 Hannah's Hope Fund 的小型非营利基金会资助。这项工作最终于 2012 年 1 月与 FDA 召开了 preIND（研究性新药）会议，并于 2013 年 6 月召开了关于拟议临床试验的 RAC 会议。预计将于 2013 年夏季提交 I 期安全性 GAN 基因治疗临床试验的 IND，重点是拯救脊髓运动和感觉神经元。该试验由汉娜希望基金 (Hannah's Hope Fund) 赞助，将在 NIH 临床中心进行，由 Carsten Bonnemann 博士指导。该 I 期试验旨在确定我们的通用 gigaxonin 基因转移方法在渴望参与且无法治疗的老年患者中的安全性。该患者群体由即将死亡或病情进展太严重而无法参加后期试验的个体组成。虽然 I 期试验正在进行中，但该提案旨在更好地描述 GAN 的特征，为 II/III 期试验提供信息，并在我们的方法需要修改时确定新的治疗靶点。此外，其目标是优化基因转移方法并开发 GAN 敲除大鼠。