Regulatable Gene Expression for Prevention of Neuropathy

描述（由申请人提供）： 化疗诱导的周围神经病变（CIPN）是许多常用抗癌药物的剂量限制性毒性，目前尚无FDA批准的预防CIPN的干预措施。在动物模型中，CIPN可以通过全身施用神经营养因子来预防，但是将这些发现转化为临床治疗受到排除全身施用的脱靶效应的限制。在过去的十年中，我们已经解决了这个问题，通过基因转移使用载体创建的复制缺陷单纯疱疹病毒（HSV），以实现局部释放的肽从背根神经节（DRG）神经元，我们的HSV载体表达前脑啡肽原现在是在2期临床试验治疗顽固性疼痛。为了在外周神经系统中安全地表达神经营养因子以用于延长时间范围的病症，能够调节转基因表达将是至关重要的。本申请中提出的研究旨在扩展我们先前的工作，以确定来自非复制型HSV载体的神经营养因子-3（NT 3）和/或白介素-10（IL 10）的调节表达是否可用于预防CIPN。

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.