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

项目摘要/摘要 化疗所致周围神经病(CIPN)是一种引起发病率的严重副作用 并限制了治疗癌症所允许的化疗剂量。在接受神经毒素治疗的患者中 化疗后，大约30-40%的患者会发生CIPN，然而发生CIPN的危险因素 人们对此知之甚少。该项目的目标是测试是否对CIPN的易感性 通过采用我们的新型CIPN-in-a-DISH神经毒理学试验进行体外预测，该方法使用IPSC- 从病人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 来源于Charcot-Marie-Tooth病(遗传性周围神经病)患者。 首先，CIPN-in-a-DISH试验将用于比较来自CMT的ISN之间的敏感性 患者和健康对照。随后，CMT样本会出现有害的基因突变 使用基因编辑技术(CRISPR/CAS)和CIPN敏感性进行比较 在病理性ISN和基因矫正的ISN之间。在第二个具体目标中，将推导出ISN 来自一组接受标准紫杉醇辅助治疗的乳腺癌患者 化疗。再次使用CIPN-in-a-DISH检测，来自明显患有 从紫杉醇中开发出的CIPN将以盲法与明显 还没有。这些研究将起到两个重要作用：1)它们是一项“原则证明”研究 这决定了这种使用患者样本的方法是否可以用于预测 个体患者，2)假设生成研究，其中患者样本将允许 对CIPN易感机制的定向研究。该技术在未来的潜在应用 技术将是使用患者自己的神经元来确定他们对神经毒素的敏感性 特定化疗的效果，从而允许为患者提供个性化的精确药物 得了癌症。

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.