Development of an Optical Silencer Based Genetic Therapy for Neuropathic Pain

描述(申请人提供)：Eos NeuroScience，Inc.与该公司的学术伙伴合作，正在开发一种结合基因疗法和光学神经调节技术的新技术，以实现对神经病理性疼痛的潜在疗法。我们公司希望，这项技术将广泛适用于美国和世界各地患有衰弱慢性疼痛的个人。简而言之，Eos神经科学公司正在创造一项技术，将通过光纤照明恢复背根神经节(DRG)中过度活跃的神经元的抑制。为此，我们正在开发一种使用腺相关病毒(AAV)的靶向传递机制，这种病毒被证明能够有效地将基因传递到DRG。我们将利用这一机制将光敏抑制质子泵靶向伤害性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的DRG的生理学。这个第一阶段项目的目标是鉴定我们可以利用普遍存在的和细胞特异性启动子将转基因传递到伤害性DRG神经元的靶向效率和特异性。然后，我们将进行电生理学来表征转导的DRG神经元中的光驱动抑制反应，以确定我们可以抑制自发多动的有效性。我们已经开始在老鼠身上进行这项测试，并将继续评估载体靶向和生理措施。因此，我们为SBIR第一期项目提出了以下具体目标：1)利用特征良好的启动子设计和构建AAV载体，用于在DRG的伤害性神经元中特异性表达光学沉默；2)通过鞘内注射将AAV载体输送到啮齿动物DRG，并通过免疫组织化学评价靶向性和毒性；3)通过细胞贴附和全细胞内记录来表征这些AAV载体在DRG中的光学沉默能力。我们非常高兴的是，从这项第一阶段研究中获得的结果将使我们能够提交第二阶段研究，最终目标是临床治疗产品。 公共卫生相关性：疼痛是一个主要的健康问题，全球有2.9亿人遭受痛苦，美国有8600万人。目前的治疗方法(如药物治疗、手术治疗、电刺激治疗和物理康复治疗)一般不能选择性地针对疼痛通路，导致严重损害身体和精神能力的不良副作用，可能包括中枢神经系统抑制、认知功能障碍、运动神经元阻断和虚弱。为此，Eos NeuroScience，Inc.和学术合作伙伴将建立一种基于基因治疗的技术，该技术可以广泛应用，使用一种光敏蛋白来沉默慢性疼痛患者感觉神经元中的直接痛感。

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.