Treatment of Peripheral Nervous System Dysfunction in Giant Axonal Neuropathy

 描述(申请人提供)：巨大轴索神经病(GAN)是一种罕见的儿童神经退行性疾病，影响中枢和周围神经系统(CNS和PNS)。大约3岁左右，患者出现进行性周围神经病变，影响感觉、运动、肠道和自主神经功能。由于目前还没有治疗方法，GAN在生命的第三个十年最终是致命的。GaN是由GaN基因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/降解中起作用的技能素蛋白。GAN的一个病理特征是大的轴突肿胀，充满了在神经系统和其他器官系统中明显存在的IF的无序聚集体。我们小组的临床前研究表明，在GAN患者成纤维细胞和GAN基因敲除(KO)小鼠中进行的GAN基因替代治疗可以清除IF聚集体。由美国国立卫生研究院赞助的一项第一阶段研究正在进行中，以测试鞘内(IT)注射scAAV9/JET-GAN治疗GAN最严重的方面，即运动和感觉神经病的安全性。然而，目前尚不清楚IT交付的scAAV9/Jet-GaN是否会治疗额外的外周靶点，如自主神经系统。这项提案的总体目标是为三叉神经节的特定组成部分确定基因替代疗法，如自主神经、肠道和躯体感觉神经组织。目标1下的实验将描述GaN KO小鼠和大鼠以及突变的GaN敲入大鼠的新的病理和行为表型。我们的初步数据首次显示，IF在GaN KO小鼠的自主神经组织中聚集，这可能模仿人类疾病的显著方面。在目标2中，我们将测试针对啮齿动物自主神经、肠道和躯体感觉系统的自然产生和工程病毒衣壳。目标3下的实验将在GAN啮齿动物模型中测试目标2中确定的治疗方法的有效性，以治疗目标1中确定的PNS特异性疾病标志物。这些研究的结果将立即适用于正在进行的GAN的第一阶段临床试验，并将有助于开发针对涉及外周和自主神经功能障碍的其他疾病的基因疗法。

 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.