Ambient light activatable opsin based therapy for age-related macular degeneration

视网膜变性会导致严重的视力丧失，就像干性老年性黄斑变性(Dry-AMD)一样 视网膜细胞功能障碍导致视觉转导周期受阻。视网膜 假体提供了恢复有限视力的可能性。然而，当前的系统受到贫穷的限制。 分辨率，随着时间的推移视网膜受损。视网膜细胞的光遗传敏化有可能作为一种过渡 直到再生医学成功为止。除了更高的分辨率，光遗传学还拥有 具有细胞特异性和微创玻璃体内注射等优点。随着环境的到来- 光激活、快速和宽带多特征光学蛋白(MCO)--临床翻译的障碍 光遗传视力恢复被移除。第二阶段的SBIR支持使我们能够完成严格的 IND-Enabling临床前研究，包括疗效、药代动力学和GLP毒性评估 玻璃体内注射vMCO在小动物和大动物体内的生物分布。这些研究是以投入为指导的 在我们的IND前会议和后续沟通中来自FDA。我们的第二阶段SBIR研究表明 该过程开发的vMCO在&gt；1年内保持稳定和有效，从而在 双极细胞。MCO剂量依赖的表达与视觉引导行为的改善高度相关 在径向水迷宫和环境光照射下的视运动反应。此外，我们在玻璃体内发现了 注射vMCO促进两种不同视网膜变性模型小鼠双极细胞MCO的表达 和大型动物。VMCO在小鼠体内的安全性得到证实，在小鼠体内未检测到视网膜光毒性 长期暴露在强光下四个月。此外，支持和反对的人数没有明显增加 注射vMCO 6个月后，观察血浆或玻璃体液中炎性细胞因子的变化。基于 这一成功和FDA的反馈，我们的目标是进一步开发用于干性视力恢复的产品(VMCO)。 环境光环境下患有视网膜营养不良的AMD受试者。这一阶段的目标-IIb SBIR 该项目将通过三个目标完成。目标1：高产量的VMCO稳健可控生产 和可比性能；目标2：评估转导疗效和视觉功能 NHP干性AMD模型的电生理学；以及目标3：一项第一阶段开放标记、剂量-升级研究 晚期干性AMD患者眼内注射vMCO的安全性和耐受性评价这 协作努力将互补的专业知识结合在一起，以解决视网膜方面的挑战性问题 退行性疾病。在完成第IIb阶段SBIR后，我们预计将推进：(I)启动阶段- 2评估效果的试验，以及(Ii)加强我们与私募股权/风险投资公司的伙伴关系，以及 制药公司正在进行商业化。这一提议的成功将导致一种新的临床方法 用于在环境光线下治疗干性AMD患者。这种基因不可知的方法将允许治疗其他 视网膜退行性疾病，如视网膜色素变性、Stargardt和视锥视杆营养不良。

Severe loss of vision occurs due to retinal degeneration as in dry age-related macular degeneration (dry-AMD) in which dysfunction of retinal cells occurs leading to blocking of the visual transduction cycle. Retinal prostheses offer the possibility of restoring limited vision. Current systems, however, are limited by poor resolution, retinal damage over time. Optogenetic sensitization of retinal cells has potential as an interim solution until the regenerative medicine is successful. In addition to higher resolution, optogenetics has advantages such as cellular specificity and minimally invasive intravitreal injection. With advent of Ambient- light activatable, fast and broadband Multi-Characteristic Opsin (MCO), the hurdle in clinical translation of optogenetic vision restoration is removed. The phase-II SBIR support has enabled us to complete rigorous IND-enabling pre-clinical studies including evaluation of efficacy, pharmacokinetics and GLP toxicity and Biodistribution of intravitreally-injected vMCO in small and large animals. These studies were guided by inputs from FDA during our pre-IND meeting and follow-up communications. Our phase-II SBIR studies demonstrate that process-developed vMCO remains stable and potent for > 1 year leading to the efficient expression in bipolar cells. MCO-dose dependent expression was highly correlated with improved visually guided behavior in radial water maze and optomotor response at ambient light illumination. Further, we found intravitreal injection of vMCO drives MCO expression in bipolar cells of two different mice models of retinal degeneration and large animals. The safety of vMCO in mice was confirmed by no detectable retinal phototoxicity after chronic exposure with intense light for four months. Further, no significant increase of pro and anti- inflammatory cytokines in plasma or vitreous humor was observed six months after vMCO injection. Based on this success and feedback from FDA, we aim to further develop the product (vMCO) for restoring vision in dry- AMD subjects with retinal dystrophies in ambient light environment. The objective of this phase-IIb SBIR project will be accomplished through three aims. Aim 1: Robust controlled production of vMCO with high yield and comparable performance; Aim 2: Evaluation of transduction efficacy and visual function using electrophysiology in dry-AMD model of NHPs; and Aim 3: A Phase 1 Open Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Intraocular vMCO injection in Patients with Advanced dry-AMD. This collaborative effort brings together complementary expertise to address a challenging problem in retinal degenerative diseases. Upon completion of the phase IIb SBIR we envision to advance: (i) Initiation of Phase- 2 trial for evaluating efficacy, and (ii) enhance our partnership with private-equity/venture capital firms and pharmaceutical company for commercialization. Success of this proposal will lead to a new clinical approach for treating patients with dry-AMD at ambient light. This gene-agnostic approach will allow treatment of other retinal degenerative diseases such as retinitis pigmentosa, Stargardt and cone-rod dystrophy.