Development of an Optical Silencer Based Genetic Therapy for Neuropathic Pain

描述（由申请人提供）：Eos Neuroscience, Inc.与公司的学术合作伙伴合作，正在开发一种结合基因治疗和光学神经调节技术的新技术，以实现神经性疼痛的潜在治疗。我们公司希望这项技术能够广泛应用于美国和世界各地患有慢性疼痛的个人。简而言之，Eos神经科学公司正在开发一种技术，该技术将通过光纤照明恢复对背根神经节（DRG）过度活跃神经元的抑制。为此，我们正在开发一种使用腺相关病毒（AAV）的靶向递送机制，该机制已被证明可以有效地将基因递送到DRG中。我们将利用这一机制靶向光敏抑制质子泵，进入伤害性DRG神经元，并研究我们的转基因的免疫组织化学定位和这些转导DRG的生理学。这个I期项目的目标是表征靶向效率和特异性，我们可以使用普遍存在的和细胞特异性启动子将我们的转基因传递到伤害性DRG神经元。然后，我们将进行电生理学来表征转导的DRG神经元的光驱动抑制反应，以确定我们可以沉默自发性多动的功效。我们已经开始在大鼠中进行这项试验，并将继续评估媒介靶向和生理措施。据此，我们提出SBIR一期工程的具体目标如下：(1)利用特性良好的启动子设计构建AAV载体，在DRG痛感神经元中特异性表达光沉默因子；(2)通过鞘内注射将AAV载体传递给啮鼠DRG，并通过免疫组化评价靶向性和毒性；(3)通过细胞贴壁和全细胞胞内记录表征AAV载体在DRG中的光沉默能力。我们非常期待从I期研究中获得的结果将使我们能够提交II期研究，最终目标是临床治疗产品。

DESCRIPTION (provided by applicant): Eos Neuroscience, Inc., in collaboration with the company's academic partners, is developing a novel technology combining gene therapeutics and optical neuromodulation techniques to enable a potential therapy for neuropathic pain. It is the hope of our company that this technology will be widely applicable and available to individuals in the United States and worldwide that suffer from debilitating chronic pain. In brief, Eos Neuroscience, Inc. is creating a technology that will restore inhibition to hyperactive neurons in the dorsal root ganglion (DRG) with fiber optic illumination. To this end, we are developing a targeted delivery mechanism using an adeno-associated virus (AAV) that is proven effective at delivering genes into DRG. We will use this mechanism to target a photosensitive inhibitory proton pump, into the nociceptive DRG neurons and study the immunohistochemical localization of our transgene and physiology of these transduced DRG. The goal of this Phase I project is to characterize the targeting efficiency and specificity with which we can deliver our transgene to nociceptive DRG neurons using ubiquitous and cell specific promoters. We will then perform electrophysiology to characterize the light driven inhibitory responses in transduced DRG neurons to determine the efficacy with which we can silence spontaneous hyperactivity. We have started this testing in rats and will continue to evaluate both vector targeting and physiological measures. Accordingly, we propose the following specific aims for our SBIR Phase I project: 1) Design and construct AAV vectors using well-characterized promoters, for specific expression of an optical silencer in nociceptive neurons of the DRG, 2) Deliver AAV vectors via intrathecal injection to rodent DRG and evaluate targeting specificity and toxicity via Immunohistochemistry, and 3) Characterize the optical silencing capability of these AAV vectors in DRG using cell attached and whole cell intracellular recording. We are very enthusiastic that results obtained from this Phase I study will enable us to submit a Phase II with the eventual goal of a clinical therapeutic product. PUBLIC HEALTH RELEVANCE: Pain is a major health problem, with 290 million people suffering worldwide and 86 million in the US. Current therapeutic approaches (e.g., pharmacological, surgical, electrical stimulation and physical rehabilitation therapy) generally fail to target pain pathways selectively, resulting in undesired side effects that can significantly impair physical and mental ability and may include central nervous system depression, cognitive dysfunction, blockade of motor neurons, and weakness. To this end, Eos Neuroscience, Inc. and academic partners will establish a gene therapy based technology that can be applied broadly using a light sensitive protein to silence pain sensation directly in sensory neurons of patients suffering from chronic pain.