Defining and treating peripheral nervous system dysfunction in Cln1 disease

Cln1 疾病周围神经系统功能障碍的定义和治疗

基本信息

批准号：
10597696
负责人：
JONATHAN D COOPER
金额：
$ 23.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597696
关键词：
Action Potentials Affect Axon Brain CLN1 gene Central Nervous System Central Nervous System Diseases Chemicals Child Childhood Data Defect Denervation Disease Disease Outcome Enzymes Etiology Event Functional disorder Genes Goals Immobilization Infantile neuronal ceroid lipofuscinosis Knowledge Life Mechanical Stimulation Mechanics Mediating Motor Mus Muscle Mutation Nature Neonatal Nerve Nervous System Neurodegenerative Disorders Neuromuscular Junction Neuronal Ceroid-Lipofuscinosis Neurons Neuropeptides Outcome Measure Pain Pain Threshold Pathology Peripheral Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Quality of life Schwann Cells Sensory Sensory Nerve Endings Severities Spielmeyer-Vogt Disease Spinal Cord Spinal Ganglia Spinal cord posterior horn Stimulus Structure Symptoms Testing Therapeutic Time Touch sensation Treatment Efficacy Treatment outcome Up-Regulation Viral Withdrawal afferent nerve clinically relevant design disease phenotype effective therapy efficacy evaluation efficacy testing gene therapy improved infancy mechanical stimulus neuron loss prevent response targeted treatment therapy outcome thioesterase PPT1 gene product treatment strategy vector

项目摘要

Abstract: CLN1 disease or Infantile Neuronal Ceroid Lipofuscinosis (INCL or Infantile Batten disease) is one of the earliest onset and most rapidly progressing forms of neuronal ceroid lipofuscinosis (NCL or Batten disease). CLN1 disease is caused by deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1), and has a devastating impact upon the central nervous system (CNS). Symptoms start within the first year of life and progress rapidly. CLN1 disease is always fatal, and there is no effective therapy. While the catastrophic effects of PPT1 deficiency upon the CNS are well appreciated, relatively little is formally known about disease phenotypes outside the brain and spinal cord. In addition to a rapid decline in motor function leading to immobility, children with CLN1 disease display diverse sensory abnormalities including altered pain thresholds and hyperexcitability to touch. Our preliminary data from CLN1 disease mice suggest these phenotypes are due to a pronounced impact of CLN1 disease upon both motor and sensory components of the peripheral nervous system (PNS) that have been previously overlooked. These include loss of peripheral axons, denervation of the neuromuscular junction, loss of non-myelinating terminal Schwann cells and compromised compound muscle action potentials, altered thresholds to mechanical stimuli, loss of dorsal root ganglia neurons and an upregulation of pain-associated neuropeptides in the dorsal horn of the spinal cord. The contribution of such PNS phenotypes to CLN1 disease outcome is poorly understood, and CNS- directed therapies are unlikely to completely treat these PNS manifestations of this disease, which may worsen over time. Now we will more thoroughly characterize the extent and nature of PNS disease before testing a gene therapy strategy capable of treating both CNS and PNS defects. We have already demonstrated that neonatal CNS delivery of an AAV2/9 vector expressing PPT1 remarkably improves brain and spinal cord function in CLN1 disease mice. We will now test whether combining CNS-targeted and systemic delivery of AAV2/9-PPT1 will provide better treatment outcomes compared to treating the CNS alone with this vector. We will achieve these goals with the following specific aims. Specific Aim 1: To determine the structural and functional integrity of the peripheral nervous system in CLN1 disease mice. Specific Aim 2: To treat peripheral nervous system disease with AAV-mediated gene therapy. Together these studies will provide detailed information about how PPT1 deficiency impacts PNS structure and function in CLN1 disease mice. Determining the efficacy of gene therapy to treat these underappreciated consequences of PPT1-deficiency outside the brain, will allow us to refine treatment strategies to improve quality of life and provide clinically relevant disease outcomes for children with CLN1 disease.

抽象的： CLN1 病或婴儿神经元蜡质脂褐质沉着症（INCL 或婴儿 Batten 病）是其中一种神经元蜡质脂褐素沉积症（NCL 或 Batten 病）最早发病且进展最快的形式。 CLN1 疾病是由溶酶体酶棕榈酰蛋白硫酯酶 1 (PPT1) 缺陷引起的，并且对中枢神经系统（CNS）具有毁灭性影响。症状在出生后第一年内出现并且进步很快。 CLN1疾病总是致命的，并且没有有效的治疗方法。虽然 PPT1 缺陷对中枢神经系统造成的灾难性影响已广为人知，但正式已知的相对较少关于大脑和脊髓以外的疾病表型。除了运动功能迅速下降患有 CLN1 疾病的儿童会表现出多种感觉异常，包括疼痛改变，导致无法活动阈值和触摸过度兴奋。我们来自 CLN1 疾病小鼠的初步数据表明这些表型是由于 CLN1 疾病对运动和感觉成分的显着影响所致以前被忽视的周围神经系统（PNS）。这些包括损失周围轴突、神经肌肉接头去神经、非髓鞘终末雪旺细胞丧失复合肌肉动作电位受损、机械刺激阈值改变、背侧肌丧失根神经节神经元和脊髓背角疼痛相关神经肽的上调绳索。这种 PNS 表型对 CLN1 疾病结果的贡献知之甚少，并且 CNS- 定向疗法不太可能完全治疗这种疾病的这些 PNS 表现，这可能会恶化随着时间的推移。现在，在测试之前，我们将更彻底地描述 PNS 疾病的程度和性质。能够治疗 CNS 和 PNS 缺陷的基因治疗策略。我们已经证明了新生儿中枢神经系统递送表达 PPT1 的 AAV2/9 载体可显着改善大脑和脊髓 CLN1 疾病小鼠中的功能。我们现在将测试是否将中枢神经系统靶向和系统性递送相结合与仅用该载体治疗中枢神经系统相比，AAV2/9-PPT1 将提供更好的治疗结果。我们将通过以下具体目标来实现这些目标。具体目标 1：确定周围神经系统的结构和功能完整性 CLN1疾病小鼠。具体目标2：利用AAV介导的基因疗法治疗周围神经系统疾病。这些研究将共同提供有关 PPT1 缺陷如何影响 PNS 结构和 CLN1 疾病小鼠中的功能。确定基因疗法治疗这些未被充分认识的疾病的功效 PPT1 缺乏在大脑外造成的后果，将使我们能够改进治疗策略以改善 CLN1 疾病儿童的生活质量并提供临床相关的疾病结果。