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

描述（由申请人提供）：本申请的总体目标是获得提交用于治疗神经性疼痛的XT-101人体临床试验的新药（IND）申请所需的剩余临床前数据。XT-101是编码人白细胞介素-10 （IL-10）的表达质粒DNA的封装制剂。对于神经性疼痛的安全有效的治疗方法存在着巨大的临床需求。目前治疗神经性疼痛的失败有效可能反映了所有这些药物明确靶向神经元的事实。在过去的二十年里，人们对神经胶质细胞激活在神经性疼痛的发展和持续中的重要性的认识日益加深，近年来，记录神经胶质细胞失调在动物模型病理性疼痛（包括神经性疼痛）中至关重要的出版物呈指数增长。对于XT-101的基本原理至关重要的是，现在在动物模型中有确凿的证据表明，疼痛的神经胶质失调是由脊髓中神经胶质促炎产物的持续释放产生和维持的。这些脊髓胶质促炎产物中最重要的是促炎细胞因子，对于一般的病理性疼痛，特别是神经性疼痛。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，靶向激活的胶质细胞和胶质促炎产物，这些胶质细胞和促炎产物负责支持和放大神经性疼痛信号。XT-101已被证明是高度有效的主要动物模型神经性疼痛。该项目的具体目标是1)为XT-101的生产制定和实施良好生产规范（GMP）流程，2)完成所有剩余的临床前研究，以支持向FDA提交IND申请，以及3)为神经性疼痛适应症的XT-101准备并向FDA提交IND申请。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，以证明XT-101在适当动物模型中的安全性，并提供指导人类剂量的信息。根据我们与FDA的IND前会议，我们期望从这些研究的成功完成中获得的数据，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.