Treatment of Peripheral Nervous System Dysfunction in Giant Axonal Neuropathy

巨大轴突神经病周围神经系统功能障碍的治疗

基本信息

批准号：
9407051
负责人：
Rachel M Bailey
金额：
$ 3.54万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2018-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407051
关键词：
3 year old Address Affect Area Autonomic Dysfunction Autonomic nervous system Axonal Neuropathy Behavioral Capsid Childhood Clinical Trials Data Dependovirus Development Disease Disease Marker Disease Progression Engineering Enteral Enteric Nervous System Fibroblasts Functional disorder Gene Targeting Genes Goals Human Intermediate Filaments Intrathecal Injections Knock-in Knock-out Knockout Mice Life Mediating Methods Monitor Motor Mutation Nerve Tissue Nervous system structure Neurodegenerative Disorders Neurological observations Pathologic Pathology Patients Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Phase I Clinical Trials Phenotype Play Proteins Rattus Recombinant adeno-associated virus (rAAV)Research Rodent Rodent Model Role Route Sensory Serotyping Structure of parasympathetic ganglion Swelling Sympathetic Ganglia System Testing Time Tissues Transgenic Organisms Translating Treatment Efficacy United States National Institutes of Health Viral adeno-associated viral vector attenuation autonomic nerve body system efficacy testing experimental study gene replacement therapy gene therapy gigaxonin human disease improved loss of function mutation motor disorder mutant nervous system disorder novel phase 1 study preclinical study preservation public health relevance safety testing sciatic nerve sensory neuropathy somatosensory targeted treatment vector

项目摘要

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.

描述（由适用提供）：巨型轴突神经病（GAN）是一种罕见的小儿神经退行性疾病，影响中枢和周围神经系统（CNS和PNS）。大约3岁大约，患者出现了一种进行性周围神经病，会影响感觉，运动，肠道和自主神经功能。由于目前不存在治疗，甘最终在生命的第三个十年中最终致命。 GAN是由GAN基因中的常染色体隐性功能突变引起的，GAN基因中编码在中间丝（IFS）的组织/降解中起作用的千氧蛋白蛋白。 GAN的病理标志是大轴突肿胀，充满了整个神经系统和其他器官系统中明显的IF的混乱骨料。我们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基因替代疗法导致清除IF聚集体。正在进行NIH赞助的I期研究，以测试鞘内（IT）SCAAV9/JET-GAN的安全性，以治疗GAN最严重的方面，即运动和感觉神经病。但是，目前尚不清楚SCAAV9/JET-GAN的输送是否将处理其他外围靶标，例如自主神经系统。该提案的总体目标是确定PNS特定组成部分的基因替代疗法，例如自主神经，肠和体感神经组织。 AIM 1下的实验将表征GAN KO小鼠以及大鼠以及突变的GAN敲击大鼠的新型病理和行为表型。我们的初步数据首次表明，Gan Ko小鼠的自主神经组织中是否有骨料，这可能模仿人类疾病的显着方面。在AIM 2下，我们将测试天然发生和工程的病毒式衣壳，以靶向啮齿动物的自主，肠和体感系统。 AIM 3下的实验将测试AIM 2中确定的疗法的效率，以治疗GAN啮齿动物模型中AIM 1中鉴定的PNS特异性疾病标志物。这些研究的结果将立即适用于GAN正在进行的1阶段临床试验，并将有助于开发基因治疗，以涉及涉及外围和自主功能障碍的其他疾病。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Erratum to: Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease.

勘误：巨大轴突神经病 (GAN) KO 小鼠自主神经系统受累：对人类疾病的影响。

DOI：
10.1007/s10286-016-0371-9
发表时间：
2016
期刊：
Clinical autonomic research : official journal of the Clinical Autonomic Research Society
影响因子：
0
作者：
Armao,Diane;Bailey,RachelM;Bouldin,ThomasW;Kim,Yongbaek;Gray,StevenJ
通讯作者：
Gray,StevenJ