Analyzing the efficacy of MMP-13 inhibitors in the treatment of CIPN

MMP-13抑制剂治疗CIPN的疗效分析

• 批准号: 10323774
• 负责人: Sandra Rieger
• 金额: $ 35.57万
• 依托单位: AVANTYX, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323774
• 关键词: ADME Study; Acute Pain; Analgesics; Animal Behavior; Animal Model; Animals; Binding; Biochemical; Biological Assay; Biological Availability; Cancer Patient; Cancer Survivor; Chemotherapy-induced peripheral neuropathy; Clinical; Collagen; Dermal; Diabetic Neuropathies; Dose; Drug Interactions; Drug Kinetics; Enzyme Precursors; Epidermis; Extracellular Matrix Degradation; Future; Goals; Hand; Health Care Costs; Healthcare Systems; Heart; Hypersensitivity; Individual; Inhibition of Matrix Metalloproteinases Pathway; Injections; Kidney; Laboratories; Lead; Liver; Long-Term Care; Lung; Mechanical Stimulation; Mechanics; Modeling; Mus; Muscle Weakness; National Cancer Institute; Neuropathy; New England; Numbness; Oral; Oral Administration; Paclitaxel; Pain; Pain Measurement; Paresthesia; Patient Care; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Phenotype; Prevention; Property; Publishing; Quality of life; Rattus; Research; Rest; Rivers; Rodent Model; Route; Sampling Studies; Scheme; Sensory; Sensory Nerve Endings; Services; Skin; Solubility; Specificity; Spleen; Symptoms; Temperature; Testing; Tissues; Topical agent; Topical application; Toxic effect; Toxicology; Tumor Burden; United States; Universities; Up-Regulation; Veterinary Pathology; Work; Zebrafish; allodynia; axon regeneration; axonal degeneration; cancer therapy; chemotherapy; collagenase 3; drug candidate; drug development; efficacy evaluation; efficacy study; experience; foot; in vivo; in vivo Model; inhibitor/antagonist; innovation; nerve damage; novel; phase 1 study; prevent; sensory mechanism; sensory neuropathy; targeted agent; therapeutic candidate; tumor growth

Project Summary The goal of this project is to establish an effective drug candidate to treat chemotherapy-induced peripheral neuropathy (CIPN). The National Cancer Institute estimates that approximately 400,000 (or ~60-70%) of patients undergoing chemotherapy suffer from CIPN. These patients may need to terminate chemotherapy treatment if experiencing symptoms, such as numbness, pain, temperature sensitivity, or tingling. Cancer survivors furthermore often have to live with CIPN for the rest of their lives. To date are no treatments available with which to tackle this problem. CIPN costs the healthcare system upward of $13B annually for long-term care of the patients. Thus, there is a significant clinical and economical need to develop drug therapies. Avantyx Pharmaceuticals, LLC has identified a new compound targeting the Matrix-Metalloproteinase 13 (MMP-13), which was shown to promote the degeneration of sensory nerve endings in animal models for CIPN induced by paclitaxel treatment. The key focus of this Phase I project is to characterize a novel MMP-13 inhibitor for its bioavailability, efficacy, specificity, and toxicity in a rat model of paclitaxel-induced peripheral neuropathy, which is following studies in which we established the efficacy of this inhibitor in zebrafish. Key goals are to establish parameters, such as optimal route of administration (oral or topical), optimal dosing, and target specificity, which is necessary to proceed to further drug development studies in Phase II.

项目摘要 该项目的目标是建立一种有效的候选药物来治疗化疗引起的外周血 神经病(CIPN)。国家癌症研究所估计，大约40万人(或~60%-70%) 接受化疗的患者患有CIPN。这些患者可能需要终止化疗。 如果出现麻木、疼痛、温度敏感或刺痛等症状，请进行治疗。癌 此外，幸存者往往不得不与CIPN共度余生。到目前为止还没有可用的治疗方法 用来解决这个问题。CIPN为医疗保健系统带来的长期成本每年超过130亿美元 照顾病人。因此，开发药物疗法具有重要的临床和经济需求。 Avantyx PharmPharmticals，LLC发现了一种针对基质的新化合物--金属蛋白酶13 (基质金属蛋白酶-13)，有促进CIPN动物模型感觉神经末梢退行性变的作用 紫杉醇治疗所致。这一阶段项目的主要焦点是表征一种新型的基质金属蛋白酶-13 紫杉醇诱导的大鼠外周模型中抑制剂的生物利用度、有效性、特异性和毒性 神经病变，这是我们在斑马鱼中确定这种抑制剂的有效性的研究之后进行的。钥匙 目标是建立参数，如最佳给药途径(口服或外用)，最佳剂量，以及 靶标特异性，这对于在第二阶段进行进一步的药物开发研究是必要的。