Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery

通过 BBB 靶向蛋白递送对 MPS I 中的中枢神经系统表现进行基因治疗

基本信息

  • 批准号:
    7567421
  • 负责人:
  • 金额:
    $ 32.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-30 至 2013-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Abstract Mucopolysaccharidosis type I (MPS I), resulting from the deficiency of alpha-L- iduronidase (IDUA), is one of the most common lysosomal storage diseases (LSD) affecting the central nervous system (CNS), which cannot be cured by current treatments. We have shown that lentiviral vector (LV)-mediated gene delivery can produce sustained supraphysiological IDUA levels in plasma and may be therapeutic in treating CNS manifestations if the blood-brain barrier (BBB) can be overcome. The utilization of the endogenous receptor-mediated transcytosis system on BBB-forming brain capillary endothelium will enable rapid and wide delivery of neurotherapeutics across the BBB via circulation. The overall goal of the work proposed is to develop a novel therapeutic approach utilizing low-density lipoprotein receptor family (LDLRf)- mediated transcytosis for fusion protein delivery across the BBB via LV-mediated gene transfer in the liver and/or the HSC for the treatment of CNS manifestations in MPS I. We will identify, by in vitro and in vivo evaluation, the optimal LDLRf-binding domain of apoE for most efficient BBB transport while retaining the normal catalytic function and lysosomal enzyme trafficking of fusion IDUA (Specific Aim 1). The spatial and temporal protein distribution profile will be studied in the CNS and peripheral organs, targeting the liver or HSC-derived erythroid cells as depot organ for tissue-specific transgene production in mice with different ages (Specific Aim 2). Preclinical evaluation will be conduced in a murine MPS I model to identify window of CNS treatment by GAG assay for metabolic correction, pathology evaluation for CNS normalization and behavioral assessments for improvement of CNS functional deficits (Specific Aim 3). Taken together, these studies will not only lead to the development of a novel approach for the treatment of neurological diseases, such as in MPS I, with lifelong BBB-targeted protein delivery, but also provide important knowledge of in vivo changes in receptor-mediated BBB transport system with aging or under pathological conditions. PUBLIC HEALTH RELEVANCE: Narrative The blood-brain-barrier has hindered the capability of rapid and wide delivery of neurotherapeutics and diagnostic agents to the central nervous system. The studies described in this application will open the door to novel approaches for the treatment of neurological disorders-from MPS type I to major public health concerns such as stroke and Alzheimer's disease.
描述(由申请人提供):

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(2)

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Dao Pan其他文献

Dao Pan的其他文献

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{{ truncateString('Dao Pan', 18)}}的其他基金

Advancing CNS drug delivery via epigenetic modulation
通过表观遗传调节促进中枢神经系统药物输送
  • 批准号:
    10679755
  • 财政年份:
    2023
  • 资助金额:
    $ 32.81万
  • 项目类别:
Manipulation of microRNA for CNS delivery: implication to treatment of neurological LSD
用于中枢神经系统递送的 microRNA 操作:对神经性 LSD 治疗的影响
  • 批准号:
    10201374
  • 财政年份:
    2020
  • 资助金额:
    $ 32.81万
  • 项目类别:
Gaucher disease:Treatment of neurodegenerative disease
戈谢病:神经退行性疾病的治疗
  • 批准号:
    8723918
  • 财政年份:
    2013
  • 资助金额:
    $ 32.81万
  • 项目类别:
Gaucher disease:Treatment of neurodegenerative disease
戈谢病:神经退行性疾病的治疗
  • 批准号:
    9290966
  • 财政年份:
    2013
  • 资助金额:
    $ 32.81万
  • 项目类别:
Gaucher disease:Treatment of neurodegenerative disease
戈谢病:神经退行性疾病的治疗
  • 批准号:
    9069618
  • 财政年份:
    2013
  • 资助金额:
    $ 32.81万
  • 项目类别:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
通过 BBB 靶向蛋白递送对 MPS I 中的中枢神经系统表现进行基因治疗
  • 批准号:
    7692967
  • 财政年份:
    2008
  • 资助金额:
    $ 32.81万
  • 项目类别:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
通过 BBB 靶向蛋白递送对 MPS I 中的中枢神经系统表现进行基因治疗
  • 批准号:
    8130702
  • 财政年份:
    2008
  • 资助金额:
    $ 32.81万
  • 项目类别:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
通过 BBB 靶向蛋白递送对 MPS I 中的中枢神经系统表现进行基因治疗
  • 批准号:
    7913103
  • 财政年份:
    2008
  • 资助金额:
    $ 32.81万
  • 项目类别:
Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery
通过 BBB 靶向蛋白递送对 MPS I 中的中枢神经系统表现进行基因治疗
  • 批准号:
    8321014
  • 财政年份:
    2008
  • 资助金额:
    $ 32.81万
  • 项目类别:
In Vivo BM Stem Cell Gene Transfer for MPS type I
针对 I 型 MPS 的体内 BM 干细胞基因转移
  • 批准号:
    6923451
  • 财政年份:
    2005
  • 资助金额:
    $ 32.81万
  • 项目类别:

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