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

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

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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疾病或婴儿神经元蛋白脂肪促脂肪促脂肪FIPOFOFOSISOS（含或婴儿the病）是其中之一最早的发病和最快进展的神经元粘膜脂肪促脂肪促脂肪促脂肪促脂肪促脂（NCL或Batten疾病）。 CLN1疾病是由溶酶体酶棕榈酰蛋白硫代酶1（PPT1）和对中枢神经系统（CNS）有毁灭性的影响。症状从生命的第一年开始并迅速发展。 CLN1疾病总是致命的，没有有效的治疗。而 PPT1缺乏症对中枢神经系统的灾难性影响得到很好的赞赏，相对较少的正式已知关于大脑和脊髓外的疾病表型。除了运动功能快速下降导致不动的，患有CLN1疾病的儿童表现出多种感觉异常，包括改变疼痛阈值和触摸过度触摸。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明显影响以前被忽略的周围神经系统（PNS）。这些包括丢失周围轴突，神经肌肉连接的修饰，非层状末端schwann细胞的丧失并破坏了复合肌肉动作电位，改变了机械刺激的阈值，背侧丧失根神经神经元和脊柱背角的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，CNS- 定向疗法不太可能完全治疗这种疾病的PNS表现，这可能会恶化随着时间的推移。现在，我们将在测试之前更彻底地表征PNS疾病的程度和性质能够治疗中枢神经系统和PNS缺陷的基因治疗策略。我们已经证明了 Neonatal CNS递送AAV2/9矢量表达PPT1明显改善大脑和脊髓 CLN1病小鼠的功能。现在，我们将测试是否合并CNS靶向和全身交付与单独使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。我们将通过以下特定目标实现这些目标。特定目的1：确定周围神经系统的结构和功能完整性 CLN1病小鼠。特定目的2：通过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缺乏症如何影响PNS结构和 CLN1病小鼠的功能。确定基因疗法的疗效治疗这些欠佳 PPT1缺陷在大脑外的后果将使我们能够完善治疗策略以改善生活质量并为患有CLN1疾病的儿童提供临床相关的疾病结局。