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：
Stefanie Geisler
金额：
$ 41.95万
依托单位：
WASHINGTON UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10349764
关键词：
Address Aftercare Axon Behavioral Bortezomib Cancer Model Cancer Patient Cancer Survivor Chemotherapy-Oncologic Procedure Chemotherapy-induced peripheral neuropathy Cisplatin Clinic Clinical Cultured Cells Dependovirus Development Disease Dominant-Negative Mutation Dose Dose-Limiting Drops Enzymes Health Hematology Hyperalgesia In Vitro Injections Intervention Knock-out Lead Life Malignant Neoplasms Mediating Metabolic Metabolism Methods Multiple Myeloma Mus Nerve Nerve Degeneration Nerve Fibers Neurology Neurons Neuropathy Niacinamide Oncology Other Genetics Paclitaxel Pain Pathogenesis Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Diseases Pharmaceutical Preparations Phosphotransferases Plasma Prevention Prevention strategy Process Proteins Quality of life Safety Savings Spinal Puncture Sterility Symptoms Therapeutic Tissues Toll-like receptors Toxic effect Translating Translations Vincristine Virus Wild Type Mouse Work analog appropriate dose axonal degeneration base cancer therapy chemotherapeutic agent chemotherapy chemotherapy induced neuropathy cofactor cost disability effective therapy effectiveness testing evidence base experimental study functional outcomes gene therapy heart metabolism improved in vivo leukemia metabolomics mouse model multidisciplinary neuroinflammation neurotransmission nicotinamide-beta-riboside novel oral supplementation overexpression prevent programs selective expression side effect success treatment duration treatment strategy tumor progression

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.

项目摘要/摘要化学疗法诱导的周围神经病（CIPN）是常见的，剂量限制的副作用化学治疗药物。 CIPN可能是令人痛苦的痛苦，令人衰弱，导致永久残疾，并导致一些患者选择结束挽救生命的治疗。与其他副作用相反，CIPN经常持续远远超出了治疗时间，可能导致永久性残疾。因此，疗法是迫切需要，因为它们不仅会在期间和之后提高癌症患者的生活质量治疗，但也通过允许有效的化学治疗剂量来改善癌症治疗。解决这个问题我们需要开发基于机制的CIPN的介入策略。化学疗法诱导的神经病的特征是轴突变性，这导致不愉快神经病的症状。我们已经证明了长春新碱和硼替佐米，两种广泛使用的化学治疗性通过神经元蛋白SARM1（A的中心执行者）的作用机理ACT的药物具有不同的作用机理基因编码的轴突变性程序。激活的SARM1裂解代谢辅助因子NAD+，导致局部NAD+消耗，然后代谢崩溃和轴突碎片。我们在这里介绍几个阻止轴突变性的最终通用途径的新策略。我们产生了一个sarm1 有效抑制SARM1功能和轴突变性的主要/负。我们将利用adeno- 相关病毒（AAV）介导的SARM1显性阴性的表达以阻断SARM1活性并将评估SARM1主导/阴性对轴突变性，神经炎症和功能的影响结果。我们已经在体外表明，增强了NAD+的合成强烈保护vincristine和硼替唑诱导的轴突变性。我们将使用NAD+打捞酶的病毒介导的表达增强NAD+合成的途径，该途径抵消了SARM1的轴突破坏性作用。作为进一步的一步转化为诊所，我们将在癌症的小鼠模型中评估我们的治疗策略是否相互作用使用癌症或化学疗法，在癌症小鼠中有效。我们的实验的成功将带领直接使用临床上可行的手段，以预防和治疗CIPN。