ENGINEERED HERPES SIMPLEX VIRUS FOR TREATMENT OF GLIOMAS

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The purpose of this Mentored Clinical Scientist Development Award application is to provide the necessary training for the principal investigator to develop into a fully independent investigator applying molecular medicine to diseases of the central nervous system (CNS). Specifically, the application proposes to engineer novel modifications into the genome of herpes simplex viruses (HSV) for the purpose of developing a safe and effective therapy for human gliomas. The development of these viruses will include foreign gene inserts to enhance the oncolytic activity of these viruses. Multiple genes from the HSV genome will he deleted to enhance the safety of this therapy. Double probes will be utilized to determine the distribution of both latent and actively replicating HSV in the CNS of treated animals. As virus constructs are developed, their biologic behavior will be evaluated in both in vitro and in vivo glioma models. This will include assessment of replication, antitumor activity, and the degree of foreign gene expression. In vivo evaluations will be conducted in both scid and c57BL/6 mice bearing intracranial gliomas to calculate the effects of immune response on tumor regression and host survival. Tissue sections will be examined to evaluate glioma eradication, neurovirulence, residual infectious virus, and immune response. Promising constructs will then be tested for neurovirulence in the HSV-sensitive simian primate, Aotus. The mentors who will direct this training proposal are international experts in herpes simplex virology and in glioma biology. The program is fully endorsed by the Division of Neurosurgery, which will provide all necessary resources. The candidate's career objective is to become a clinician-scientist who both 1) develops new models for the treatment of neurological diseases based on molecular medicine and 2) bridges basic science and clinical medicine by bringing such therapies into clinical use. An integral portion of the training program will thus be aimed at developing expertise in the design and administration of clinical trials. The candidate's immediate goals are to participate in an organized program that will provide the necessary training to become a fully independent investigator in this area while studying a novel therapy for brain tumors.