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: 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
• 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

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 化疗引起的周围神经病变(CIPN)是一种常见的、经常是剂量限制的副作用 化疗药物。CIPN可以是极度痛苦、极度虚弱、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期间，并可导致永久性残疾。因此，治疗方法是 因为它们不仅将提高癌症患者在治疗期间和治疗后的生活质量 治疗，但也通过允许有效的化疗剂量来改进癌症治疗。要解决这个问题 需要我们为CIPN开发基于机制的干预策略。 化疗引起的神经病变的特征是轴突变性，这会导致不愉快的 神经病的症状。我们已经证明了长春新碱和硼替佐米这两种广泛使用的化疗药物 具有不同作用机制的代理人通过神经元蛋白Sarm1发挥作用，Sarm1是一种 基因编码的轴突变性程序。激活的Sarm1裂解代谢辅因子NAD+， 导致局部NAD+耗竭，随后代谢崩溃和轴突碎裂。我们在这里介绍几个 阻止轴突退化这一最终共同途径的新策略。我们生成了一个Sarm1 显性/负性，有效抑制Sarm1功能和轴突变性。我们将使用腺- 联合病毒(AAV)介导的Sarm1显性阴性表达阻断Sarm1活性和意志 评估Sarm1显性/阴性对轴突变性、神经炎症和功能的影响 结果。我们在体外已经证明，促进NAD+的合成对长春新碱和 硼替佐米诱导的轴突变性。我们将使用病毒介导的NAD+挽救酶的表达 促进NAD+合成的途径，对抗Sarm1的轴突破坏效应。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 与癌症或化疗有关，对荷瘤小鼠有效。我们实验的成功将导致 直接提供临床上可行的预防和治疗CIPN的手段。