Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy

开发基于机制的策略来治疗化疗引起的周围神经病变

基本信息

  • 批准号:
    10349764
  • 负责人:
  • 金额:
    $ 41.95万
  • 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:
    2022-01-13 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently dose-limiting side-effect of chemotherapeutic drugs. CIPN can be excruciatingly painful, profoundly debilitating, cause permanent disability, and lead some patients to elect to end life-saving treatment. In contrast to other side effects, CIPN frequently lasts well beyond the duration of treatment and can cause permanent disability. Consequently, therapies are urgently needed as they would not only enhance the quality of life of cancer patients both during and after treatment, but also improve cancer therapy by permitting effective chemotherapeutic dosing. To address this need we have developed mechanism-based interventional strategies for CIPN. Chemotherapy-induced neuropathies are characterized by axonal degeneration, which leads to the unpleasant symptoms of neuropathies. We have shown that vincristine and bortezomib, two widely used chemotherapeutic agents with different mechanisms of action act via the neuronal protein SARM1, the central executioner of a genetically encoded axon degeneration program. Activated SARM1 cleaves the metabolic cofactor NAD+, leading to local NAD+ depletion, followed by metabolic collapse and axon fragmentation. We here present several new strategies to block this final common pathway to axon degeneration. We generated a SARM1 dominant/negative that potently inhibits SARM1 function and axon degeneration. We will utilize adeno- associated virus (AAV) -mediated expression of a SARM1 dominant-negative to block SARM1 activity and will assess the effect of SARM1-dominant/negative on axon degeneration, neuroinflammation and functional outcomes. We have shown in vitro that boosting the synthesis of NAD+ strongly protects against vincristine and bortezomib-induced axon degeneration. We will use virus-mediated expression of enzymes of the NAD+ salvage pathway to boost NAD+ synthesis, which counters the axon destructive effects of SARM1. As a further step to translation to the clinic, we will evaluate in mouse models of cancer whether our therapeutic strategies interact with the cancer or chemotherapy and are effective in cancer-bearing mice. Success of our experiments will lead directly to clinically viable means to prevent and treat CIPN.
项目总结/摘要 化疗诱导的周围神经病变(CIPN)是化疗的常见、经常剂量限制性副作用。 化疗药物CIPN会带来极度的痛苦,严重的衰弱,导致永久性残疾, 并导致一些患者选择结束挽救生命的治疗。与其他副作用相比,CIPN经常 持续时间远远超过治疗的持续时间,并可能导致永久性残疾。因此, 他们迫切需要,因为他们不仅可以提高癌症患者在治疗期间和治疗后的生活质量, 治疗,而且还通过允许有效的化疗剂量来改善癌症治疗。为了解决这个 我们需要为CIPN制定基于机制的干预策略。 化疗引起的神经病变的特点是轴突变性,这导致了令人不快的 神经病变的症状。我们已经证明,长春新碱和硼替佐米,两种广泛使用的化疗药物, 具有不同作用机制的药物通过神经元蛋白SARM 1起作用,SARM 1是一种神经元蛋白的中央执行者。 基因编码的轴突退化程序活化的SARM 1切割代谢辅因子NAD+, 导致局部NAD+耗尽,随后是代谢崩溃和轴突断裂。我们在这里介绍几个 新的策略来阻断轴突退化的最终共同途径。我们生成了一个SARM 1 显性/阴性,有效抑制SARM 1功能和轴突变性。我们会利用腺- 相关病毒(AAV)介导的SARM 1显性阴性表达以阻断SARM 1活性,并将 评估SARM 1-显性/阴性对轴突变性、神经炎症和功能的影响。 结果。我们已经在体外证明,促进NAD+的合成强烈地保护长春新碱, 硼替佐米诱导的轴突变性。我们将使用病毒介导的NAD+补救酶的表达, 途径来促进NAD+的合成,从而对抗SARM 1的轴突破坏作用。作为进一步的步骤, 翻译到临床,我们将在小鼠癌症模型中评估我们的治疗策略是否相互作用, 与癌症或化学疗法,并在荷癌小鼠有效。我们实验的成功将导致 直接用于临床上可行的预防和治疗CIPN的方法。

项目成果

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Stefanie Geisler其他文献

Stefanie Geisler的其他文献

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{{ truncateString('Stefanie Geisler', 18)}}的其他基金

Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy
开发基于机制的策略来治疗化疗引起的周围神经病变
  • 批准号:
    10550224
  • 财政年份:
    2022
  • 资助金额:
    $ 41.95万
  • 项目类别:
Sarm1 Pathway: New Therapeutic Targets in Neuropathy
Sarm1 通路:神经病的新治疗靶点
  • 批准号:
    8868459
  • 财政年份:
    2015
  • 资助金额:
    $ 41.95万
  • 项目类别:

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