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:
  • 金额:
    $ 23.63万
  • 依托单位:
  • 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

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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项目成果

期刊论文数量(0)
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JONATHAN D COOPER其他文献

JONATHAN D COOPER的其他文献

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{{ truncateString('JONATHAN D COOPER', 18)}}的其他基金

Systems-Level Approach to Neuronopathic Lysosomal Storage Disorders
神经病性溶酶体贮积症的系统级方法
  • 批准号:
    10721768
  • 财政年份:
    2023
  • 资助金额:
    $ 23.63万
  • 项目类别:
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
  • 批准号:
    10428174
  • 财政年份:
    2022
  • 资助金额:
    $ 23.63万
  • 项目类别:
Characterizing and testing the efficacy of AAV-mediated gene therapy in a sheep model of CLN1 disease.
在 CLN1 疾病绵羊模型中表征和测试 AAV 介导的基因治疗的功效。
  • 批准号:
    10339842
  • 财政年份:
    2022
  • 资助金额:
    $ 23.63万
  • 项目类别:
Characterizing and testing the efficacy of AAV-mediated gene therapy in a sheep model of CLN1 disease.
在 CLN1 疾病绵羊模型中表征和测试 AAV 介导的基因治疗的功效。
  • 批准号:
    10671454
  • 财政年份:
    2022
  • 资助金额:
    $ 23.63万
  • 项目类别:
Characterizing and testing the efficacy of AAV-mediated gene therapy in a novel CRISPR/Cas9 generated sheep model of Cln1 disease.
在新型 CRISPR/Cas9 生成的 Cln1 疾病绵羊模型中表征和测试 AAV 介导的基因治疗的功效。
  • 批准号:
    10357987
  • 财政年份:
    2021
  • 资助金额:
    $ 23.63万
  • 项目类别:
Comparative Morphology of Neuronal Ceroid Lipofuscinosis
神经元蜡质脂褐质沉积症的比较形态学
  • 批准号:
    6618013
  • 财政年份:
    2002
  • 资助金额:
    $ 23.63万
  • 项目类别:
Comparative Morphology of Neuronal Ceroid Lipofuscinosis
神经元蜡质脂褐质沉积症的比较形态学
  • 批准号:
    6789345
  • 财政年份:
    2002
  • 资助金额:
    $ 23.63万
  • 项目类别:
Comparative Morphology of Neuronal Ceroid Lipofuscinosis
神经元蜡质脂褐质沉积症的比较形态学
  • 批准号:
    6471081
  • 财政年份:
    2002
  • 资助金额:
    $ 23.63万
  • 项目类别:

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