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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.

项目总结/文摘