Treatment of Peripheral Nervous System Dysfunction in Giant Axonal Neuropathy

 描述（由申请方提供）：巨轴突神经病（GAN）是一种罕见的儿科神经退行性疾病，影响中枢和外周神经系统（CNS和PNS）。大约3岁时，患者表现为影响感觉、运动、肠和自主神经功能的进行性周围神经病变。GAN在生命的第三个十年最终是致命的，因为目前没有治疗方法。GAN是由GAN基因中的常染色体隐性功能丧失突变引起的，GAN基因编码在中间丝（IF）的组织/降解中起作用的gigaxonin蛋白。GAN的病理学标志是大的轴突，充满了在整个神经系统和其他器官系统中明显的IF的无序聚集体。我们小组的临床前研究表明，GAN患者成纤维细胞和GAN敲除（KO）小鼠中的GAN基因替代疗法导致IF聚集体的清除。NIH赞助的I期研究正在进行中，以测试scAAV 9/JeT-GAN的鞘内（IT）递送的安全性，以治疗GAN的最严重方面，即运动和感觉神经病变。然而，目前尚不清楚scAAV 9/Jet-GAN的IT递送是否会治疗其他外周靶点，例如自主神经系统。该提案的总体目标是确定PNS特定成分的基因替代疗法，如自主神经、肠神经和体感神经组织。目标1下的实验将表征GAN KO小鼠和大鼠以及突变GAN敲入大鼠的新病理和行为表型。这是第一次，我们的初步数据显示IF聚集在GAN KO小鼠的自主神经组织中，这可能模拟了人类疾病的突出方面。根据目标2，我们将测试天然存在的和工程病毒衣壳靶向啮齿动物的自主神经，肠道和体感系统。目标3下的实验将测试目标2中确定的疗法在GAN啮齿动物模型中治疗目标1中确定的PNS特异性疾病标志物的功效。这些研究的结果将立即适用于正在进行的GAN 1期临床试验，并将有助于开发涉及外周和自主神经功能障碍的其他疾病的基因治疗。

 DESCRIPTION (provided by applicant): Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disorder that affects both the central and peripheral nervous systems (CNS and PNS). Around 3 years of age, patients present with a progressive peripheral neuropathy that affects sensory, motor, enteric and autonomic nerve function. GAN is ultimately fatal by the third decade of life as no treatment currently exists. GAN is caused by autosomal recessive loss-of- function mutations in the GAN gene, which encodes for the gigaxonin protein that plays a role in the organization/degradation of intermediate filaments (IFs). A pathological hallmark of GAN is large axonal swellings filled with disorganized aggregates of IFs that are apparent throughout the nervous system and other organ systems. Preclinical studies by our group show that GAN gene replacement therapy in GAN patient fibroblasts and GAN knock-out (KO) mice results in the clearance of IF aggregates. An NIH-sponsored Phase I study is underway to test the safety of Intrathecal (IT) delivery of scAAV9/JeT-GAN to treat the most severe aspects of GAN, namely the motor and sensory neuropathy. It is currently unknown, however, if IT delivery of scAAV9/Jet-GAN will treat additional peripheral targets, such as the autonomic nervous system. The overall objectives of this proposal are to identify gene replacement therapies for specific components of the PNS, such as autonomic, enteric and somatosensory nervous tissues. Experiments under Aim 1 will characterize novel pathological and behavioral phenotypes of GAN KO mice and rats and mutant GAN knock-in rats. For the first time, our preliminary data shows IF aggregate in the autonomic nervous tissues of GAN KO mice, which may mimic salient aspects of the human disease. Under Aim 2 we will test naturally occurring and engineered viral capsids for targeting of the autonomic, enteric and somatosensory systems of rodents. Experiments under Aim 3 will test the efficacy of the therapies identified in Aim 2 to treat the PNS-specific disease markers identified in Aim 1 in GAN rodent models. Results from these studies will be immediately applicable to the ongoing Phase 1 clinical trial for GAN and will aid in the development of gene therapy for additional disorders involving peripheral and autonomic dysfunction.