Stem cell-derived exosomes to ameliorate chemobrain

摘要 大量的临床和临床前研究已经证实了衰弱的神经认知方面 各种化疗方案治疗癌症的效果，通常被称为 化疗枪。随着癌症幸存者数量的大幅增加，在 仅在美国，癌症治疗后的认知功能被认为是最关键的功能之一 评价治疗结果和确定长期生活质量的标准。这个 情况因明显缺乏令人满意的治疗方法而进一步混乱 与非中枢神经系统癌症治疗相关的进行性神经认知后遗症。这 应用程序响应特定的RFA(PAR-21-329)以调查设计的干预措施 预防或减少癌症治疗后的不良神经认知后遗症。我们的前- 临床研究显示慢性化疗的长期后果 (环磷酰胺，CYP；阿霉素，ADR单一疗法)包括认知障碍，损失 神经结构、脊椎完整性和神经炎症。我们假设神经性炎症 是长期中枢神经系统功能障碍的主要因素之一，人类神经 干细胞(HNSC)来源的细胞外小泡(EVS)治疗可以改善不良反应 化疗相关的神经认知和炎症性后遗症。我们最近的数据显示 HNSCs或hNSC来源的EV逆转肿瘤治疗(CYP或放疗，IRR)诱导 认知障碍，神经元和脊椎损伤，以及神经炎症。静脉内(回溯) 眶静脉注射hNSC-EVS对IRR脑有长期的神经保护作用。我们 还在EV货物中确定了候选miRNA，其基因靶标与 在暴露的癌症治疗中观察到的分子、结构和行为改善 EV注射后的动物。重要的是，miR-124-3p在体内的表达逆转了IRR- 诱发的认知缺陷和神经炎症。基于上述，我们提出了一个 全面的系列研究旨在测试hNSC-EV的有效性并确定 基于EV衍生候选miRNA的机制改善化学颗粒和 常规辅助化疗方案(卡铂-紫杉醇，ADR- 控制卵巢癌和乳腺癌的生长。我们的研究设计将描绘出长期的- RO注射HSNC-EV或体内表达miR-124-3p的长期神经保护作用 在无病或异种移植癌小鼠模型中遵循辅助化疗方案。 这些研究还将阐明hNSC-EVS治疗的安全性、毒性和药代动力学。 在癌症的背景下。因此，这个项目是建立在强大的出版和 初步数据支持我们的理论。

ABSTRACT Numerous clinical and preclinical studies have established the debilitating neurocognitive side effects of various chemotherapy regimens for the treatment of cancer, often referred as chemobrain. With substantial increases in the number of cancer survivors, over 16.9 million in the U.S. alone, cognitive function following cancer treatment is considered as one of the most critical criterion for evaluating therapeutic outcome and for determining long-term quality of life. The situation is confounded further by the conspicuous absence of satisfactory treatments for reducing the progressive neurocognitive sequelae associated with non-CNS cancer therapies. This application is in response to a specific RFA (PAR-21-329) to investigate interventions designed to prevent or reduce the adverse neurocognitive sequelae following cancer therapy. Our pre- clinical studies have shown long-term consequences of chronic chemotherapy (cyclophosphamide, CYP; Adriamycin, ADR monotherapy) including cognitive impairments, loss of neuronal architecture, spine integrity and neuroinflammation. We posit that neuroinflammation is one of the major contributory factors for long-term CNS dysfunction and that human neural stem cell (hNSC)-derived extracellular vesicle (EVs) treatment can ameliorate adverse neurocognitive and inflammatory sequelae associated with chemobrain. Our recent data show that hNSCs or hNSC-derived EV reverse cancer therapy (CYP or irradiation, IRR)-induced cognitive impairments, neuron and spine damage and, neuroinflammation. Intra-venous (retro- orbital vein, RO) injections of hNSC-EVs showed long-term neuroprotection in the IRR brain. We have also identified candidate miRNA within the EV cargo, with gene targets relevant to the molecular, structural and behavioral improvements observed in the cancer therapy-exposed animals following EV injection. Importantly, in vivo expression of miR-124-3p reversed IRR- induced cognitive deficits and neuroinflammation. Based on the foregoing, we propose a comprehensive series of studies designed to test the effectiveness hNSC-EV and determine an EV-derived candidate miRNA-based mechanism to ameliorate chemobrain and neuroinflammation in routinely used adjuvant chemotherapy regimens (Carboplatin-Taxol, ADR- CYP) to control the growth of ovarian and breast cancer. Our research design will delineate long- term neuroprotective effects of RO injections of hSNC-EV or in vivo expression of miR-124-3p following adjuvant chemotherapy regimens in disease-free or xenograft cancer mouse models. These studies will also elucidate the safety, toxicity and pharmacokinetics of hNSC-EVs therapy in the context of cancer. Thus, this project is based on a foundation of strong published and preliminary data supporting our rationale.