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: 9763518
• 负责人: Nathan P Staff
• 金额: $ 35.28万
• 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/9763518
• 关键词: Address; Adjuvant; Advanced Malignant Neoplasm; 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; cell immortalization; 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; side effect; stem cell technology

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.

项目摘要/摘要 化学疗法诱导的周围神经病（CIPN）是一种严重的副作用，导致发病率 并限制了允许治疗癌症的化学疗法剂量。那些接受神经毒性的人 化学疗法，大约30-40％的患者发展为CIPN，但发展的风险因素 这是很熟悉的。该项目的目的是测试是否可以对CIPN的敏感性 通过使用我们使用IPSC- 从患者样本中得出的感觉神经元。在第一个特定目标中，感觉神经元（ISN）将 源自患有charcot-marie-tooth病（遗传性周围神经病）的患者。 首先，将使用cipn-in-dish测定法比较CMT的ISN之间的敏感性 患者和健康对照。随后，CMT样品将具有其有害基因突变 使用基因编辑技术（CRISPR/CAS）和CIPN敏感性纠正 在病理IS和基因校正的ISN之间。在第二个特定目标中，IS将被得出 来自已接受标准可调节紫杉醇的乳腺癌患者的队列 化学疗法。再次使用cipn-in-a-dish测定法，没有明显的患者 从紫杉醇开发的CIPN将以盲目的方式与显然的患者进行比较 没有。这些研究将发挥两个重要功能：1）它们是“原理证明”研究 这决定了使用这种使用患者样品的方法是否可以用于预测CIPN 个人患者，2）一项假设生成研究，其中患者样本将允许 CIPN敏感性机制的定向研究。此的潜在应用 技术将使用患者自己的神经元来确定其对神经毒性的敏感性 特定化学疗法的影响，从而为患者提供个性化的精确药物 癌症。