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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要化疗引起的周围神经病变 (CIPN) 是一种导致发病的严重副作用并限制接受神经毒性治疗的癌症患者的化疗剂量。化疗后，大约 30-40% 的患者会出现 CIPN，但发生 CIPN 的危险因素人们对这一点知之甚少，该项目的目的是测试是否可以检测对 CIPN 的敏感性。通过采用我们新型 CIPN-in-a-dish 神经毒理学测定（使用 iPSC-）进行体外预测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) 将从患者样本中提取。源自患有腓骨肌萎缩症（遗传性周围神经病）的患者。首先，CIPN-in-a-dish 检测将用于比较来自 CMT 的 iSN 之间的敏感性随后，患者和健康对照者的样本中都会出现有害的基因突变。使用基因编辑技术 (CRISPR/Cas) 进行校正并比较 CIPN 敏感性在第二个具体目标中，将得出病理 iSN 和基因校正 iSN 之间的关系。来自接受标准紫杉醇辅助治疗的乳腺癌患者队列再次使用 CIPN-in-a-dish 检测，iSN 来自已明确接受化疗的患者。由紫杉醇开发的 CIPN 将以盲法方式与明确的患者进行比较这些研究将发挥两个重要作用：1）它们是一项“原理验证”研究。确定这种使用患者样本的方法是否可以用于预测 CIPN 个体患者，2) 患者样本允许的假设生成研究 CIPN 易感性机制的定向研究其潜在的未来应用。技术将利用患者自身的神经元来确定他们对神经毒性的敏感性特定化疗的效果，从而为患者提供个性化精准医疗患有癌症。