Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease

脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究

基本信息

  • 批准号:
    9893931
  • 负责人:
  • 金额:
    $ 67.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT A major barrier to effective treatment of the central nervous system (CNS) in most inherited diseases is that pathology is present throughout the brain because the metabolic defect is present in most brain cells. Thus, global distribution of the gene or gene product is required. Several gene therapy strategies are being investigated for treatment of global brain lesions. However, all of the approaches have significant shortcomings, which become apparent in large animal models of human diseases. Development of more effective treatments in these models will facilitate translation into clinical usage. This project will investigate AAV vector mediated gene delivery into the brain by infusion into the cerebrospinal fluid (CSF), which can result in disseminated delivery of a gene in a large animal brain. The disease model to be evaluated is alpha-mannosidosis (AMD) in the cat, a lysosomal storage disorder (LSD) caused by mutations in the lysosomal enzyme (LE) structural gene, alpha-mannosidase (MANB). The strategy for treatment is based on cross-correction, in which transfer of a normal copy of the MANB cDNA into AMD cells results in the metabolic correction of those gene-transduced cells. Furthermore, the genetically corrected cells release normal MANB enzyme, which is taken up by surrounding cells and corrects them metabolically as well. This well-established cross-correction mechanism is the basis for treatments of most LSDs. The disease progression and improvement from treatment will be monitored in living animals by clinical neurological assessment, life-span increases, serum and CSF analyses, and non-invasive brain imaging by magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI). In post-mortem animals, the disease correction will be analyzed quantitatively for distribution of vector transduction, increases in MANB enzymatic activity, reduction of mannose-containing oligosaccharide substrate accumulation, histopathological changes, and potential adverse host responses. We will address important issues affecting translation by investigating strategies to attain more complete correction of the brain: in Aim 1 we will investigate the effects of alternative routes of CSF delivery; in Aim 2 we will investigate the effects of dose escalation on the extent of resolution of pathology; and in Aim 3 we will determine the effectiveness of therapy when initiated at progressively more severe stages of disease to evaluate the potential to ameliorate advanced disease.
摘要

项目成果

期刊论文数量(0)
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JOHN H WOLFE其他文献

JOHN H WOLFE的其他文献

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{{ truncateString('JOHN H WOLFE', 18)}}的其他基金

Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
  • 批准号:
    10379947
  • 财政年份:
    2019
  • 资助金额:
    $ 67.49万
  • 项目类别:
Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
  • 批准号:
    9763064
  • 财政年份:
    2019
  • 资助金额:
    $ 67.49万
  • 项目类别:
Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease
脑脊液(CSF)定向基因治疗全球神经代谢性脑疾病的转化研究
  • 批准号:
    10599930
  • 财政年份:
    2019
  • 资助金额:
    $ 67.49万
  • 项目类别:
Disseminated gene delivery to the CNS by human iPSC-derived neural stem cells
通过人类 iPSC 衍生的神经干细胞将播散性基因传递至 CNS
  • 批准号:
    9204865
  • 财政年份:
    2015
  • 资助金额:
    $ 67.49万
  • 项目类别:
Disseminated gene delivery to the CNS by human iPSC-derived neural stem cells
通过人类 iPSC 衍生的神经干细胞将播散性基因传递至 CNS
  • 批准号:
    8894955
  • 财政年份:
    2015
  • 资助金额:
    $ 67.49万
  • 项目类别:
Disseminated gene delivery to the CNS by human iPSC-derived neural stem cells
通过人类 iPSC 衍生的神经干细胞将播散性基因传递至 CNS
  • 批准号:
    8997131
  • 财政年份:
    2015
  • 资助金额:
    $ 67.49万
  • 项目类别:
Gene Transfer and NMR Studies in Alpha-Mannosidosis Brain
α-甘露糖苷沉积症脑中的基因转移和核磁共振研究
  • 批准号:
    8068082
  • 财政年份:
    2010
  • 资助金额:
    $ 67.49万
  • 项目类别:
Project 1
项目1
  • 批准号:
    8102896
  • 财政年份:
    2010
  • 资助金额:
    $ 67.49万
  • 项目类别:
Stem Cell Transplantation for Neurogenetic Disease
干细胞移植治疗神经遗传性疾病
  • 批准号:
    7459697
  • 财政年份:
    2007
  • 资助金额:
    $ 67.49万
  • 项目类别:
Stem Cell Transplantation for Neurogenetic Disease
干细胞移植治疗神经遗传性疾病
  • 批准号:
    8094219
  • 财政年份:
    2007
  • 资助金额:
    $ 67.49万
  • 项目类别:

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降低儿童和青少年高风险药物的儿科不良事件风险:提高牙科诊所中儿科患者的安全
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