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首页> 外文学位 >Gene therapy and enzyme replacement in a mouse model of late infantile neuronal ceroid lipofuscinosis.
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Gene therapy and enzyme replacement in a mouse model of late infantile neuronal ceroid lipofuscinosis.

机译：晚期婴儿神经元类固醇脂褐藻病小鼠模型中的基因治疗和酶替代。

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摘要

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a pediatric neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal protease tripeptidyl peptidase 1 (TPP1). As there is no known therapy, patients suffer motor and cognitive decline, and premature death. Existing murine and canine models of LINCL are suitable for testing novel therapies. The goals of my thesis were to identify relevant neuropathological and behavioral phenotypes in the TPP1-deficient mouse model, and develop therapeutic strategies for rescuing those phenotypes.;In the TPP1-deficient mouse, we characterized reactive astrocytosis in the brain and identified degenerating neuron populations that may contribute to the motor deficits of the mouse. We also developed a sensitive behavioral assay that detects an age-dependent increase in resting tremor. These quantifiable phenotypes were then used to assess efficacy in an enzyme replacement study.;Intravenous enzyme replacement is beneficial for some lysosomal storage diseases, but not for those with central nervous system (CNS) involvement, as enzymes do not efficiently cross the blood brain barrier. The cerebrospinal fluid offers an alternative route of enzyme delivery to the CNS. We tested the efficacy of intraventricular enzyme delivery to the TPP1-deficient mouse and observed that infusion of recombinant TPP1 restored enzyme activity throughout the brain and rescued disease phenotypes in the mouse.;Finally, we developed gene therapy strategies for treating CNS disease. In addition to evaluating the gene transfer properties of several adeno-associated virus (AAV) serotypes in the mouse and dog LINCL models, we also took a novel approach in which we redirected the tissue tropism of AAV to the cerebral vasculature, which we hypothesized could be co-opted for enzyme delivery to the CNS. We used in vivo phage display to screen for peptides that bind to the vasculature of the TPP1-deficient mouse, then inserted these peptides into the AAV capsid. Importantly, the resulting virus expressed TPP1 from the cerebral vasculature following intravenous injection. These vectors are now being tested in ongoing efficacy studies.;In summary, our findings illustrate novel approaches to treating CNS disease and lay the foundation for future pre-clinical studies.
机译：晚期婴儿神经元类脂褐质病（LINCL）是一种小儿神经退行性疾病，由CLN2突变​​引起，该突变编码溶酶体蛋白酶三肽基肽酶1（TPP1）。由于没有已知的疗法，患者会遭受运动和认知功能下降以及过早死亡。 LINCL的现有鼠类和犬类模型适用于测试新型疗法。本文的目的是在TPP1缺陷型小鼠模型中识别相关的神经病理学和行为表型，并制定挽救这些表型的治疗策略。在TPP1缺陷型小鼠中，我们对大脑中的反应性星形细胞增多症进行了表征，并鉴定了退化的神经元群体。这可能会导致鼠标的运动功能障碍。我们还开发了一种敏感的行为分析，可检测静息性震颤的年龄依赖性增加。然后将这些可量化的表型用于评估酶替代研究的功效。静脉酶替代对某些溶酶体贮积病有益，但对中枢神经系统（CNS）受累者则无益，因为酶不能有效地穿过血脑屏障。脑脊液提供了另一种酶传递至中枢神经系统的途径。我们测试了脑室内向TPP1缺陷型小鼠体内递送酶的功效，并观察到重组TPP1的注入恢复了整个大脑的酶活性，并挽救了小鼠的疾病表型。最后，我们开发了用于治疗CNS疾病的基因治疗策略。除了评估小鼠和狗LINCL模型中几种腺相关病毒（AAV）血清型的基因转移特性外，我们还采用了一种新颖的方法，将AAV的组织定向性重定向至脑血管系统，我们认为这可以可以选择将酶递送至CNS。我们使用了体内噬菌体展示来筛选与TPP1缺陷型小鼠的血管系统结合的肽，然后将这些肽插入AAV衣壳中。重要的是，静脉注射后，所得病毒从脑血管中表达TPP1。这些载体目前正在进行中的功效研究中进行测试。总之，我们的发现阐明了治疗中枢神经系统疾病的新方法，并为未来的临床前研究奠定了基础。

著录项

  • 作者

    Chang, Michael Chia Hsiu.;

  • 作者单位

    The University of Iowa.;

  • 授予单位 The University of Iowa.;
  • 学科 Biology Molecular.;Biology Genetics.;Biology Neurobiology.;Biology Physiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 155 p.
  • 总页数 155
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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