REPLICONS ENCODING SUICIDE GENES AS THERAPIES FOR GLIOMA

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The prognosis for patients diagnosed with malignant glioma has remained very poor despite recent advances in traditional surgical, radiation, and chemical therapies. Novel suicide gene therapies for gliomas have shown promise in pre-clinical studies; however, the development of effective delivery systems is critical to ensure their success. We believe that encapsidated RNA-based replicons are an attractive alternative vector to the traditional ones being pursued for these treatments because of their transient nature in vivo, rapid onset of protein expression, inability to spread or cause disease in the host, and lack of DNA intermediates in the replication cycle, which eliminates the possibility of insertional mutagenesis. In this phase I application, we propose to test the efficacy of using replicon vectors that express herpesvirus thymidine kinase, purine nucleoside phosphorylase, or cytosine deaminase for suicide gene therapy of gliomas in mouse model systems. These vectors will be evaluated alone and in combinations to identify the replicon-based suicide gene cocktail that best promotes survival and inhibition of tumor growth. These studies employ relevant mouse model systems for brain tumors and should form the foundation of a Phase II proposal with the goal of bringing encapsidated replicons to the marketplace as a vector for brain tumor therapies. PROPOSED COMMERCIAL APPLICATION Traditional therapies for malignant gliomas have met with little success, and patients diagnosed with these tumors survive for less than one year on average. Considering that 15,000 Americans are diagnosed with these tumors annually, resulting in 11,000 deaths, effective treatments are needed. We believe that encapsidated replicons encoding suicide genes are a promising, novel treatment with great commercial potential.