Giant Axonal Neuropathy Gene Therapy

描述（由申请人提供）：巨轴索神经病（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（IFs）紊乱，在生命的第三个十年时致命。这种疾病的病理是由于编码蛋白千轴蛋白的GAN基因的纯合子功能缺失突变。潜在的病理是由于干扰素的紊乱和积累，包括静脉蛋白、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，最严重（和致命）的GAN症状是脊髓和DRG中运动和感觉神经元功能障碍和死亡的结果。其他组织如大脑、自主神经和外周器官中IF功能障碍的表型贡献尚不清楚。自2008年以来，我们一直在开发一种基因转移方法，通过鞘内输送AAV9/GAN载体来治疗GAN，完全由一家名为汉娜希望基金的小型非营利基金会资助。这一努力最终在2012年1月与FDA召开了pre - ind（正在研究的新药）会议，并在2013年6月召开了RAC会议，以进行拟议的临床试验。预计将于2013年夏季提交I期安全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。这项试验由汉娜希望基金会赞助，将在美国国立卫生研究院临床中心进行，由卡斯滕·博纳曼博士指导。这项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。这些患者群体由即将死亡或病情进展过快而无法参与晚期试验的个体组成。虽然I期试验正在进行中，但该提案旨在以更好的方式表征GAN，从而为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。进一步优化基因转移方法，培育GAN基因敲除大鼠。

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.