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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.

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