Stem cell-derived exosomes to ameliorate chemobrain

干细胞衍生的外泌体改善化学脑

• 批准号: 10584374
• 负责人: Munjal M Acharya
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584374
• 关键词: Adjuvant Chemotherapy; Adriamycin PFS; Adult; Amygdaloid structure; Animals; Architecture; Behavioral; Brain; Cancer Model; Cancer Survivor; Carboplatin; Caring; Chemotherapy-Oncologic Procedure; Chronic; Cisplatin; Clinical; Clinical Data; Clinical Research; Cognitive deficits; Cranial Irradiation; Cyclophosphamide; Data; Disease; Doxorubicin; Drug Kinetics; Effectiveness; Emotional; Foundations; Functional disorder; Gene Targeting; Genes; Growth; Hippocampus; Human; Impaired cognition; Impairment; In Vitro; Incidence; Inflammation; Inflammatory; Injections; Intravenous; Malignant Neoplasms; Malignant neoplasm of ovary; Medial; Mediating; MicroRNAs; Modeling; Molecular; Mus; Neurobiology; Neurocognitive; Neurodegenerative Disorders; Neurons; Paclitaxel; Pathologic; Patients; Performance; Play; Publishing; Quality of life; Radiation therapy; Regimen; Research Design; Role; Safety; Series; Signal Transduction; Structure; Survivors; Synapses; Temporal Lobe; Testing; Therapeutic; Toxic effect; Transgenic Mice; Translating; Transplantation; Treatment-Related Cancer; Validation; Veins; Vertebral column; Xenograft procedure; cancer therapy; candidate identification; caregiver stress; chemobrain; chemoradiation; chemotherapy; cognitive function; cognitive task; coping; density; effectiveness testing; extracellular vesicles; frontal lobe; improved; in vivo; irradiation; malignant breast neoplasm; mouse model; nerve stem cell; neurogenesis; neuroinflammation; neuron loss; neuroprotection; novel; novel therapeutic intervention; pre-clinical; preclinical study; prevent; protein expression; regenerative approach; response; safety testing; side effect; socioeconomics; stem cell exosomes; stem cells; therapy design; therapy outcome

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.

摘要 许多临床和临床前研究已经建立了衰弱的神经认知方面 用于治疗癌症的各种化疗方案的效果，通常被称为 化学基因随着癌症幸存者人数的大幅增加， 美国癌症治疗后的认知功能被认为是最关键的因素之一。 评价治疗结果和确定长期生活质量的标准。的 这种情况进一步被明显缺乏令人满意的治疗方法所混淆， 与非CNS癌症治疗相关的进行性神经认知后遗症。这 应用程序是对特定RFA（PAR-21-329）的响应，以调查设计的干预措施 以预防或减少癌症治疗后的不良神经认知后遗症。我们的预- 临床研究表明长期化疗的长期后果 （环磷酰胺，顺铂;阿霉素，ADR单药治疗），包括认知障碍、丧失 神经结构、脊柱完整性和神经炎症。我们认为神经炎症 是长期CNS功能障碍的主要促成因素之一， 干细胞（hNSC）衍生细胞外囊泡（EV）治疗可改善不良反应 神经认知和炎症后遗症。我们最近的数据显示 hNSC或hNSC衍生的EV逆转癌症治疗（放疗或辐射，IRR）诱导的 认知障碍、神经元和脊柱损伤以及神经炎症。静脉内（逆行） 眶静脉，RO）注射hNSC-EV显示了IRR脑中的长期神经保护作用。我们 还鉴定了EV货物中的候选miRNA，其基因靶点与 在暴露于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- 3 p的体内表达逆转了IRR-1。 导致认知缺陷和神经炎症。基于上述情况，我们提出了一个 旨在测试hNSC-EV的有效性并确定 基于EV衍生的候选miRNA的改善趋化因子的机制， 在常规使用的辅助化疗方案中的神经炎症（卡铂-泰素，ADR- 控制卵巢癌和乳腺癌的生长。我们的研究设计将描绘长期- RO注射hSNC-EV或体内表达miR-124- 3 p的长期神经保护作用 在无病或异种移植癌症小鼠模型中的辅助化疗方案后。 这些研究还将阐明hNSC-EV治疗的安全性、毒性和药代动力学 in the context上下文of cancer癌症.因此，这个项目是基于一个强大的出版和 初步数据支持我们的理论。