Regulatable Gene Expression for Prevention of Neuropathy

Veterans Health Administration, Decatur PA

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Abstract

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is the dose-limiting toxicity for many commonly utilized classes of anti-cancer agents, and there are no currently available FDA-approved interventions to prevent CIPN. In animal models CIPN can be prevented by systemic administration of neurotrophic factors, but translating these findings into a clinical treatment has been limited by off-target effects that preclude systemic administration. Over the past decade we have addressed this issue by gene transfer using vectors created from replication incompetent herpes simplex virus (HSV) to achieve local release of peptides from dorsal root ganglion (DRG) neurons, and our HSV vector expressing preproenkephalin is now in a phase 2 clinical trial for treatment of intractable pain. To safely express neurotrophic factors n the peripheral nervous system for a condition that extends over a prolonged timeframe, it will be essential to be able to regulate transgene expression. Studies proposed in this application are designed to extend our previous work to determine whether regulated expression of either neurotrophin-3 (NT3) and/or interleukin-10 (IL10) from non-replicating HSV vectors can be used to prevent CIPN.