XT-101: A Novel and Potent Non-Opioid Treatment for Neuropathic Pain

描述(由申请人提供)：这项建议的总体目标是获得提交XT-101用于治疗神经性疼痛的人体临床试验的研究新药(IND)申请所需的剩余临床前数据。XT-101是编码人白介素10(IL-10)的表达载体DNA的封装配方。对于神经性疼痛的安全和有效的治疗，临床上有巨大的需求尚未得到满足。目前的治疗方法未能有效地治疗神经病理性疼痛，这可能反映了这样一个事实，即所有这些药物都明确地针对神经元。在过去的二十年里，人们越来越多地认识到神经胶质细胞激活在神经病理性疼痛的发展和持续中的重要性，多年来指数级增长的出版物记录了神经胶质细胞失调在包括神经病理性疼痛在内的动物模型中的关键重要性。XT-101的理论基础的关键是这样一个事实，即现在在动物模型中确凿地证明，神经胶质对疼痛的失调是通过脊髓中神经胶质促炎产物的持续释放而产生和维持的。对于病理性疼痛，尤其是神经病理性疼痛，这些脊髓神经胶质促炎产品中最重要的是促炎细胞因子。XT-101通过诱导强大的抗炎细胞因子IL-10的长时间产生和释放，靶向于激活的胶质细胞和负责支持和放大神经病理性疼痛信号的胶质促炎产物。XT-101已被证明在神经病理性疼痛的领先动物模型中非常有效。该项目的具体目标是1)开发和实施生产XT-101的良好制造规范(GMP)流程，2)完成所有剩余的临床前研究，以支持向FDA提交IND，以及3)准备并向FDA提交神经病理性疼痛适应症的XT-101的IND。为了实现这些目标，该项目提出了一系列研究，包括标准毒理学研究，将在适当的动物模型中证明XT-101的安全性，并提供指导人类剂量的信息。根据我们在IND前与FDA的会议，我们预计从成功完成这些研究中获得的数据，以及支持XT-101安全性和有效性的大量现有数据，将足以支持向FDA提交IND申请。

DESCRIPTION (provided by applicant): The overall aim of this proposal is the acquisition of the remaining pre-clinical data required for submission of an Investigational New Drug (IND) application for a human clinical trial of XT-101 for the treatment of neuropathic pain. XT-101 is an encapsulated formulation of an expression plasmid DNA encoding human interleukin-10 (IL-10). There is a tremendous unmet clinical need for safe and effective treatment for neuropathic pain. The failure of current therapeutics to treat neuropathic pain effectively may reflect the fact that all of these agents explicitly target neurons. Over the last two decades, there has been a growing understanding of the importance of glial activation in the development and persistence of neuropathic pain, with exponentially increasing numbers of publications across years documenting the critical importance of glial dysregulation in animal models pathological pain, including neuropathic pain. Critical to the rationale for XT-101 is the fact that it is now solidly documented across animal models that glial dysregulation of pain is created and maintained by the perseverant release of glial pro-inflammatory products in spinal cord. The most important of these spinal glial pro-inflammatory products, for pathological pain in general and for neuropathic pain in particular, are pro- inflammatory cytokines. XT-101, by inducing prolonged production and release of the powerful anti- inflammatory cytokine, IL-10, targets the activated glial cells and glial proinflammatory products that are responsible for supporting and amplifying neuropathic pain signals. XT-101 has been shown to be highly efficacious in the leading animal models for neuropathic pain. The specific aims for this project are to 1) Develop and implement good manufacturing practice (GMP) process for production of XT-101, 2) Complete all remaining pre-clinical studies necessary to support the filing of an IND with the FDA, and 3) Prepare and file an IND with the FDA for XT-101 in a neuropathic pain indication. To achieve these aims, the project proposes a series of studies, including standard toxicology studies that will demonstrate the safety of XT-101 in appropriate animal models and provide information to guide human dosing. Based on our pre-IND meeting with the FDA, we expect that the data obtained from the successful completion of these studies, along with the substantial existing data supporting the safety and efficacy of XT- 101, will be sufficient to support the filing of an IND with the FDA.