Glioblastoma multiforme (GBM), the most common primary brain malignancy, carries a grim prognosis. Currently, there are no effective treatments for this disease. Gene therapy has been long time considered as a promising approach for this disease, which, however, has not seen much progress over the past many decades. This can be potentially attributed to two major factors, including: 1) the lack of approaches for simultaneously overcoming the blood-brain barrier (BBB) for drug delivery to the brain and the cellular barriers for induction of genetic materials to cells with adequate efficiency; and 2) the lack of molecular targets that can also be effectively manipulated for elimination of GBM tumor cells, including the stem-like cells within the bulk cell population. Here, we propose testing a new strategy that is designed for adequately overcoming these hurdles: autocatalytic delivery of brain tumor-targeted nanoparticles loaded with Cas9/sgRNAs designed for elimination of genes that regulate the survival of bulk cell population as well as the stem-like cell population within GBM. In preliminary work, we proposed and tested an innovative mechanism for systemic drug delivery to the brain, called autocatalytic brain tumor-targeted (ABTT) delivery, based on which we synthesized ABTT nanoparticles (NPs) using a novel solid polymer. We demonstrated that ABTT NPs efficiently overcome the BBB and the cellular barrier and were capable of mediating effective gene therapy for treatment of brain tumors. Along this progress, we identified a group of genes through a genome wide RNAi screening as novel candidates for GBM gene therapy. In addition, we demonstrated that Cas9/sgRNA-mediated genetic knockout allowed producing more persistent inhibitory effects than the traditional RNAi approach. Based on this progress, we propose to test our strategy by optimizing and characterizing ABTT NPs for systemic delivery of Cas9/sgRNAs to GBM in Aim 1, characterizing and selecting genes with excellent biological activity in inhibition of GBM in Aim 2, and determining the therapeutic benefit of systemic gene therapy in Aim 3. Successful completion of the proposed study will establish a novel regimen for effective treatment of patients with GBM.

Public Health Relevance

GBM is the most common primary malignant brain tumors in adults. More than 18,500 new cases are diagnosed in the United States each year. This research project will result in new approaches for improved treatment of patients with this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Fountain, Jane W
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Yale University
Schools of Medicine
New Haven
United States
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