Stem cell-derived exosomes to ameliorate chemobrain

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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.