Neural stem cells (NSCs) have recently been recognized as a cellular vehicle for newer forms of brain tumor therapy. NSCs have a remarkable ability to migrate throughout the CNS towards tumors. Our primary research interest is in engineering regulatable therapeutic genes and delivering them to brain tumors. Inherently linked to the brain tumor therapy paradigm, we also use activatable optical imaging techniques to image stem cell or viral delivery and to monitor the effect of therapeutic genes delivered to brain tumors. My current research directions are:

Engineering neural stem cells for in vivo detectable marker genes and therapeutic proteins that have apoptotic and antiangiogenic effect on brain tumors:We are using neural stem cells to populate primary tumors and their microsatelite deposits and also engineer NSCs (i) to express marker genes detectable in vivo; (ii) to secrete therapeutic protein, S-TRAIL (secreted Tumor necrosis factor receptor-apoptosis inducing ligand) to specifically induce apoptosis in tumor cells and regulatable anti-angiogenic proteins to inhibit tumor angiogenesis. We are constructing a number of lentiviral vectors encoding different marker, apoptotic and antiangiogenic genes. NSCs are infected ex-vivo with different lentiviral vectors before implanting them into the brains of tumor bearing animals.

Novel agents to image the fate of exogenously administered neural stem cells:Previously we have used firefly luciferase (Fluc) imaging to track NSCs in the brain. We are now developing ways to study the differentiation potential of NSCs into different cell types in response to glioblastomas. We are using ubiquitously expressed firefly luciferase as a marker for NSC mass, whereas Renilla luciferase (Rluc) will be used under different promoters as differentiation markers.

Combination therapy with TRAIL and MMPs:To improve the transport and efficacy of S-TRAIL within gliomas, we are currently working on delivering regulatable MMPs to brain tumors. The regulatable systems are based on controlling the secretion of proteins by redirecting them into the endoplasmic reticulum (ER) of the cells using the FKBP-furin cleavage system. MMPs are reversibly retained in the ER until selectively released by a cell-permeant CAD (conditional aggregation domains)-ligand and furin, a ubiquitously expressed protease in the trans-golgi.

RNAi based therapy of brain tumors:Testing the therapeutic efficacy of RNA interference (RNAi)-based therapy directed at the human EGFR and antiapoptotic Bcl2 in mice with brain tumors. RNAi is a new form of antisense therapy wherein an expression plasmid encodes for a short hairpin RNA (shRNA) that is composed of a stem-loop structure. This shRNA is processed in the cell to an RNA duplex with a 3'-overhang, and this short RNA duplex mediates RNAi or post-transcriptional gene silencing. We are using lentiviral vectors encoding for an shRNA directed at a specific sequence in the human EGFR, antiapoptotic Bcl2 and firefly luciferase mRNA.