Giant Axonal Neuropathy Gene Therapy

描述(申请人提供)：巨大轴索神经病(GAN，OMIM#256850)是一种罕见的慢性神经退行性疾病，其特征是轴突增大并伴有无序的微管和中间丝(IF)，该疾病在出生第三个十年时会致命。这种疾病的病理是由于编码生长素蛋白的GaN基因纯合功能丧失突变所致。其潜在的病理基础是IF的解体和积聚，包括波形蛋白、α-内联蛋白、神经细丝、外周蛋白和GFAP。GAN患者的认知功能正常，最严重(和致命)的症状是脊髓和DRG中运动神经元和感觉神经元的功能障碍和死亡。IF功能障碍在其他组织，如脑、自主神经和外周器官中的表型贡献还知之甚少。自2008年以来，我们一直在开发一种通过鞘内注射AAV9/GaN载体来治疗GaN的基因转移方法，该方法完全由一个名为Hannah‘s Hope Fund的小型非营利性基金会资助。这一努力在2012年1月与FDA召开了一次IND(研究新药)预会议，并在2013年6月为一项拟议的临床试验召开了一次RAC会议。IND将于2013年夏天提交一项安全的GaN基因疗法临床试验，重点是抢救脊髓运动神经元和感觉神经元。这项试验由Hannah‘s Hope Fund赞助，将在NIH临床中心进行，由Carsten Bonnemann博士指导。这项第一阶段试验的目的是确定我们的普通生长素基因转移方法在渴望参与或无法治疗的老年患者中的安全性。这些患者群体由将死亡或疾病进展太快而无法参与后期试验的个人组成。虽然第一阶段的试验正在进行中，这项建议旨在更好地描述GaN的特征，以便为第二/第三阶段试验提供信息，并在我们的方法需要修改时确定新的治疗靶点。此外，它的目标是优化基因转移方法，并培育出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.