Giant Axonal Neuropathy Gene Therapy

标题：巨大轴索神经病的基因治疗 摘要 巨大轴索神经病是一种罕见的慢性神经退行性疾病 以轴突增大为特征，伴有无序的微管和中间丝(IF)； 这在生命的第三个十年是致命的。这种疾病的病理是由于纯合子丢失- GAN基因的功能突变，该基因编码蛋白质技加素。潜在的 病理是由于IF的解体和积聚，包括波形蛋白、α- 网织蛋白、神经细丝、外周蛋白和GFAP。GAN患者认知功能正常， 而最严重(也是最致命)的GaN症状是由于 脊髓和背根节的运动神经元和感觉神经元。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 人们对此知之甚少。自2008年以来，我们一直在开发一种基因转移方法来治疗 使用鞘内递送AAV9/GaN载体的GaN，完全由一个小型非营利性组织资助 该基金会名为汉娜希望基金。这一努力最终以PreIND(调查新的 药品)于2012年1月与FDA举行会议，并于年举行RAC会议以进行拟议的临床试验 2013年6月。提交安全GaN基因治疗I期临床试验的IND是 预计将于2013年夏天推出，重点是抢救脊髓运动神经元和感觉神经元。 由Hannah‘s Hope Fund赞助，这项试验将在NIH临床中心根据 卡斯滕·邦纳曼博士的指导。这项第一阶段的试验旨在确定我们的 普通生长素基因转移方法在渴望参与和治疗的老年患者中的应用 否则就无法治愈。这个病人群体是由死亡或死亡的个体组成的 在他们的疾病方面取得了很大的进展，以参与后来的试验。虽然第一阶段试验是 正在进行中，这项提议旨在更好地描述GaN，以提供第二阶段/第三阶段的信息 如果我们的方法需要修改，还可以确定新的治疗靶点。此外，它还 目的是优化基因转移途径，培育GaN基因敲除大鼠。

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.