Chemically produced neural progenitors as a delivery vehicle for anti-glioma therapy

Glioblastoma multiformeGBMis the most common and aggressive brain cancer with a dismal prognosis and ayear survival rateIn the past decadein vitro and in vivo studies have demonstrated that neural stem cellsNSCsneural progenitor cellsNPCsand mesenchymal stem cellsMSCspossess an inherent tropism toward invasive malignancies within the brainincluding GBMThese stem cells track down cancer cells in the tumor mass as well as migratory cancer cells in the brain parenchymaWhile several of these reports suggest that both stem cell types can be used as a diagnostic tool for gliomas and or as a delivery vehicle for glioma therapyrecent studies demonstrate several advantages of NSCs over MSCsThe disadvantage of NSCs is the lack of an adequate NSC source and approaches to produce NSCs by induced pluripotent stem celliPSCtechnologies are fraught with incalculable risksThusidentification of easyfastand safe methods for production of patient specific NSCs and NPCs and further modification of these cells to increase their tropism to gliomas could lead to the generation of highly specific and effective tools for diagnosisvisualizationand treatment of gliomasIn our previous studies we have demonstrated that MSCs derived from human adipose tissuehAMSCsexhibit high migratory ability towards gliomas in vitroand this tropism can be further enhanced by preconditioning these stem cells with glioma conditioned mediaGCMIn additionthe delivery of a therapeutic agent such as bone morphogenetic proteinBMPby hAMSCs has been shown to terminally differentiate brain tumor initiating cellsBTICsthe culprits of GBM relapse and metastasisand significantly prolong survivalThese data prompted us to elucidate whether NPCs could acquire even greater and more specific tropism to gliomas when preconditioned with GCM and if they could deliver the extraordinary therapeutic modality that is BMPTo this endNPCs generated from human bone marrow MSCsBM hMSCsor hAMSCs via a chemical approach have been usedWe found that chemically induced NPCsCiNPCsderived from hAMSCs exhibited higher migratory capacity to GCM compared to hAMSCsand preconditioning with GCM improved their migratory abilityThusCiNPCs produced by our recently developed safefastreproducibleand cost effective cell reprogramming approach could be an ideal BMPdelivery vehicle for glioma therapiesThe goals of this SBIR phase I proposal are to investigate the tropism of GCM preconditioned and lentiviral BMPtransduced CiNPCsLV BMPCiNPCsto the DMG cell line and two BTIC glioma cell lines in vitroSpecific Aimand to test whether they can be utilized as vehicles for delivery of BMPto intracranial human glioma xenografts in rodentsSpecific AimPhase II studies will investigate the therapeutic efficacy of LV BMPCiNPCs on different types of gliomasCommercial and clinically compatible research products emerging from Phase I II work include technology for large scale clinical grade production of LV BMPCiNPCs that possess specific tropism to gliomas Several recent investigations have focused on the unique tumor tropic properties of stem cells as a novel platform for targeted delivery of anticancer agents to the brainRecentlywe have been able to produce neural progenitor cellsNPCsfrom human adult mesenchymal stem cellsMSCsby safeefficientand cost effective method and demonstrated their specific high migratory capacity to gliomas in vitroThe goals of this SBIR phase I proposal are to investigate the tropism of lentiviral BMPtransduced NPCs to the glioma cell lines in vitro and to test whether they can be utilized as vehicles for delivery of BMPto intracranial human glioma xenografts in rodents