Successful treatment of human glioma, the most deadly brain tumor, has not been achieved in large part because of deficiencies in current delivery strategies. To improve delivery, we have exploited the unique properties of bone marrow-derived, human mesenchymal stem cells (hMSCs) to overcome the deficiencies of current delivery methods. We have shown that hMSCs localize to gliomas after systemic and local administration. Mouse MSCs (mMSCs) behave similarly in syngeneic models that mimic transplant into immunocompetent subjects. Other studies show that tumor-derived factors, particularly PDGF-BB, may mediate the tropism hMSCs have for gliomas. Importantly, we have also demonstrated that hMSCs engineered to release interferon-beta (IFN-beta) have powerful anti-glioma effects in an animal model of this disease. On the basis of these data, we hypothesize that human bone marrow-derived mesenchymal stem cells can be used as delivery vehicles for treatment of gliomas and that hMSCs engineered to release IFN-beta are effective anti-glioma agents. To help achieve our long-term goal of applying this approach to patients, we propose a series of studies that are expected to provide fundamental biological information necessary for translating this investigational approach to patients. Thus, to test our hypothesis, we will determine the survival, proliferation, and differentiation of hMSCs within and outside gliomas by tracking donor hMSCs in sex mismatched recipient glioma intracranial xenografts; non-invasive imaging will also be used to follow in real time the fate of systemically administered hMSCs in individual subjects. Additionally, to better mimic autologous transplantation, the capacity of mMSCs to survive within and outside gliomas will be explored in syngeneic, immunocompetent mice (Aim 1). To evaluate the mechanisms underlying the tropism of hMSCs for gliomas, we will define the extent to which specific tumor-derived factors, identified during preliminary in vitro studies, contribute to the attraction of hMSCs for glioma in vivo (Aim 2). Lastly, the efficacy and toxicity of IFN-beta-engineered MSCs will be analyzed in xenograft intracranial models of human glioma and in immunocompetent syngeneic mouse model; measurements of intratumoral and systemic IFN-beta levels will define the extent to which hMSC-delivery improves the therapeutic index of IFN-beta (Aim 3). Successful use of hMSCs to deliver therapeutic proteins to brain tumors will represent a major step forward in enhancing treatments of patients with this deadly disease for whom only minimally-effective therapies are currently available. ? ? ?
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