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
- 来源:
- 关键词:Action PotentialsAffectAxonBrainCLN1 geneCentral Nervous SystemCentral Nervous System DiseasesChemicalsChildChildhoodDataDefectDenervationDiseaseDisease OutcomeEnzymesEtiologyEventFunctional disorderGenesGoalsImmobilizationInfantile neuronal ceroid lipofuscinosisKnowledgeLifeMechanical StimulationMechanicsMediatingMotorMusMuscleMutationNatureNeonatalNerveNervous SystemNeurodegenerative DisordersNeuromuscular JunctionNeuronal Ceroid-LipofuscinosisNeuronsNeuropeptidesOutcome MeasurePainPain ThresholdPathologyPeripheralPeripheral NervesPeripheral Nervous SystemPeripheral Nervous System DiseasesPhenotypeQuality of lifeSchwann CellsSensorySensory Nerve EndingsSeveritiesSpielmeyer-Vogt DiseaseSpinal CordSpinal GangliaSpinal cord posterior hornStimulusStructureSymptomsTestingTherapeuticTimeTouch sensationTreatment EfficacyTreatment outcomeUp-RegulationViralWithdrawalafferent nerveclinically relevantdesigndisease phenotypeeffective therapyefficacy evaluationefficacy testinggene therapyimprovedinfancymechanical stimulusneuron losspreventresponsetargeted treatmenttherapy outcomethioesterase PPT1 gene producttreatment strategyvector
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.
摘要:
CLN 1疾病或婴儿神经元蜡样脂褐质沉积症(INCL或婴儿巴滕病)是其中一种
神经元蜡样质脂褐质沉积症(NCL或Batten病)的最早发作和最快速进展形式。
CLN 1疾病是由溶酶体酶棕榈酰蛋白硫酯酶-1(PPT 1)的缺乏引起的,并且
对中枢神经系统(CNS)有毁灭性的影响。症状开始于生命的第一年
并且进展迅速。CLN 1疾病总是致命的,并且没有有效的治疗方法。而
PPT 1缺陷对中枢神经系统的灾难性影响是众所周知的,但对它的正式了解相对较少
关于大脑和脊髓以外的疾病表型。除了运动功能迅速下降外
导致不动,CLN 1疾病的儿童表现出多种感觉异常,包括疼痛改变,
阈值和对触摸的过度兴奋。我们从CLN 1疾病小鼠的初步数据表明,
表型是由于CLN 1疾病对运动和感觉成分的显著影响
周围神经系统(PNS)是以前被忽视的。这些损失包括:
外周轴突,神经肌肉接头的去神经支配,非髓鞘化终末雪旺细胞的丢失
和受损的复合肌肉动作电位,改变阈值的机械刺激,损失的背
根神经节神经元和脊髓背角疼痛相关神经肽的上调
线.这种PNS表型对CLN 1疾病结果的贡献知之甚少,CNS-
定向治疗不太可能完全治疗这种疾病的这些PNS表现,
随着时间现在,我们将更彻底地描述PNS疾病的程度和性质,然后再进行测试。
能够治疗CNS和PNS缺陷的基因治疗策略。我们已经证明,
表达PPT 1的AAV 2/9载体的新生儿CNS递送显著改善脑和脊髓
在CLN 1疾病小鼠中的功能。我们现在将测试是否结合CNS靶向和系统性递送
与用该载体单独治疗CNS相比,AAV 2/9-PPT 1将提供更好的治疗结果。我们
将通过以下具体目标实现这些目标。
具体目标1:确定周围神经系统的结构和功能完整性,
CLN 1疾病小鼠。
具体目标2:用AAV介导的基因治疗治疗周围神经系统疾病。
这些研究将共同提供有关PPT 1缺陷如何影响PNS结构的详细信息,
在CLN 1疾病小鼠中的功能。确定基因疗法治疗这些被低估的疾病的疗效
PPT 1缺乏症在脑外的后果,将使我们能够改进治疗策略,
生活质量,并为患有CLN 1疾病的儿童提供临床相关的疾病结局。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
6471081 - 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:
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