Bone marrow derived neural stem cell therapy for glioma

Cedars-Sinai Medical Center, West Hollywood CA

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Abstract

DESCRIPTION (provided by applicant): The capacity of neural stem cells (NSC) to migrate towards areas of tissue damage within the brain underscores the potential use of these cells as agents for cell replacement and/or drug delivery in the brain. Malignant gliomas consist of infiltrating tumor cells, which are largely refractory to currently employed therapies, resulting in inevitable tumor recurrence. We have demonstrated the efficacy of using primary fetal murine NSC as delivery vehicles for cytotoxic or immunostimulatory agents to treat infiltrating glioma and have demonstrated a mechanism of glioma tropism. We also described a rapid culture process whereby multipotent neural precursors, phenotypically and morphologically distinct from bone marrow stromal cells can be generated from unfractionated adult bone marrow. These bone marrow derived neural progenitors (BM-NSC) are morphologically and phenotypically indistinguishable from fetal NSC and could differentiate into neurons, astrocytes, and oligodendroglia. BM-NSC demonstrated tumor tropic behavior in vivo and when inoculated into the hippocampus, engrafted and assumed neuronal phenotype. These findings indicate that adult bone marrow may serve as a viable source of neural progenitor cells to treat glioma and neurodegeneration. We now aim to test the hypotheses that: 1) Bone marrow derived NSC (BM-NSC) migration toward glioma is dependent on CXCR4 expression on the plasma membrane of BM-NSC. 2) BM-NSC differentiation into A2B5+, GFAP+ astrocytic precursors will promote migration toward glioma, while terminal differentiation into neurons will promote engraftment after intracranial transplantation. 3) Overexpression of Shh or Gli-1 will promote BM-NSC proliferation, while Nurr1 will promote neuronal fate and Delta-like ligand 1 will promote astrocytic fate. 4) Promoting BM-NSC proliferation and astrocytic fate will (i) lead to increased migration to glioma and (ii) increase tumor control and prolong survival in an experimental rodent glioma model.