Regulatable Gene Expression for Prevention of Neuropathy

描述(由申请人提供)： 项目摘要/摘要化疗引起的周围神经病变(CIPN)是许多常用抗癌药物的剂量限制性毒性，目前还没有FDA批准的干预措施来预防CIPN。在动物模型中，CIPN可以通过全身给予神经营养因子来预防，但将这些发现转化为临床治疗一直受到排除全身给予的非靶点效应的限制。在过去的十年里，我们通过使用复制不能的单纯疱疹病毒(HSV)创建的载体进行基因转移，实现了背根节(DRG)神经元多肽的局部释放，解决了这个问题，我们的HSV载体表达前脑啡肽原，目前正处于治疗顽固性疼痛的第二阶段临床试验。为了在外周神经系统中安全地表达神经营养因子，在一种持续时间较长的情况下，能够调控转基因表达是必不可少的。本申请中提出的研究旨在扩展我们之前的工作，以确定非复制型HSV载体中神经营养素-3(NT3)和/或白介素10(IL10)的调节表达是否可以用于预防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.