Assessment of Chemotherapy-Induced Peripheral Neuropathy Susceptibility Using Patient-derived iPSC Technology

使用患者来源的 iPSC 技术评估化疗引起的周围神经病变的易感性

• 批准号: 9450944
• 负责人: Nathan P Staff
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9450944
• 关键词: Address; Adjuvant; Advanced Malignant Neoplasm; Adverse effects; Afferent Neurons; Axon; Biological Assay; Biological Models; Blinded; CRISPR/Cas technology; Cell Line; Charcot-Marie-Tooth Disease; Chemotherapy-induced peripheral neuropathy; Clustered Regularly Interspaced Short Palindromic Repeats; Cohort Studies; Complication; Defect; Development; Disease; Distal; Dose; Dose-Limiting; Enrollment; Fibroblasts; Frequencies; Future; Gene Mutation; Genes; Genetic Predisposition to Disease; Goals; Human; Human Biology; In Vitro; Inherited; Lead; Malignant Neoplasms; Methodology; Microfluidics; Modeling; Morbidity - disease rate; Neurologic; Neurons; Numbness; Outcome; Paclitaxel; Pain; Pathologic; Patients; Peripheral Nervous System Diseases; Precision therapeutics; Predisposition; Regimen; Risk Factors; Rodent; Sampling; Severities; Skin; System; Technology; Testing; adult stem cell; base; cancer therapy; chemotherapy; clinical phenotype; cohort; design; experimental study; gene correction; genetic association; healthy volunteer; immortalized cell; individual patient; induced pluripotent stem cell; malignant breast neoplasm; neuronal cell body; neuroprotection; neurotoxic; neurotoxicity; neurotoxicology; novel; precision medicine; predictive modeling; prevent

PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that causes morbidity and limits the dose of chemotherapy allowed to treat cancers. Of those receiving neurotoxic chemotherapy, approximately 30-40% of patients develop CIPN, yet the risk factors for developing this are poorly understood. The goal of this project is to test whether susceptibility to CIPN can be predicted in vitro by employing our novel CIPN-in-a-dish neurotoxicology assay that uses iPSC- derived sensory neuron from patient samples. In the first Specific Aim, sensory neurons (iSN) will be derived from patients with Charcot-Marie-Tooth disease (hereditary peripheral neuropathy). First, the CIPN-in-a-dish assay will be used to compare susceptibility between iSN from CMT patients and healthy controls. Subsequently CMT samples will have their deleterious gene mutation corrected using gene-editing technology (CRISPR/Cas) and CIPN susceptibility will be compared between the pathologic iSN and gene-corrected iSN. In the second Specific Aim, iSN will be derived from a cohort of patients with breast cancer that have received standard adjuvant paclitaxel chemotherapy. Again using the CIPN-in-a-dish assay, iSN from patients that have clearly developed CIPN from paclitaxel will be compared in a blinded fashion with patients that clearly have not. These studies will serve two important functions: 1) they are a “proof-of-principle” study that determines whether this approach using patient samples can be used to predict CIPN in individual patients, 2) a hypothesis-generating study wherein patient samples will allow for directed studies of mechanisms of CIPN susceptibility. The potential future application of this technology will be to use a patient's own neurons to determine their susceptibility to the neurotoxic effects of specific chemotherapy, thus allowing for personalized precision medicine for the patient with cancer.

项目总结/摘要 化疗引起的周围神经病变（CIPN）是一种严重的副作用，导致发病率 并限制了治疗癌症的化疗剂量。在接受神经毒素的人中， 化疗后，约30-40%的患者发生CIPN，但发生CIPN的风险因素 人们对此知之甚少。该项目的目标是测试是否可以对CIPN的易感性进行评估。 通过使用我们的新型CIPN-在-皿神经毒理学测定法，使用iPSC- 从患者样本中提取感觉神经元。在第一个特定目标中，感觉神经元（iSN）将 来自Charcot-Marie-Tooth病（遗传性周围神经病）患者。 首先，将使用CIPN培养皿试验比较CMT的iSN之间的敏感性 患者和健康对照。随后CMT样本将有其有害的基因突变 将比较使用基因编辑技术（CRISPR/Cas）和CIPN敏感性进行校正 病理性iSN和基因校正iSN之间的差异。在第二个具体目标中，将导出iSN 从接受标准辅助紫杉醇的乳腺癌患者队列中 化疗再次使用CIPN-在-皿测定，iSN从患者， 将以盲法将紫杉醇引起的CIPN与明确 没有。这些研究将发挥两个重要作用：1）它们是一项“原理证明”研究 确定这种使用患者样本的方法是否可用于预测CIPN， 个体患者，2）假设生成研究，其中患者样品将允许 CIPN易感性机制的定向研究。未来的潜在应用 这项技术将利用病人自己的神经元来确定他们对神经毒素的敏感性， 特异性化疗的效果，从而为患者提供个性化的精准医疗 得了癌症