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

基于环境光激活视蛋白的治疗年龄相关性黄斑变性

• 批准号: 10256368
• 负责人: Samarendra Kumar Mohanty
• 金额: $ 74.95万
• 依托单位: NANOSCOPE TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256368
• 关键词: Address; Age related macular degeneration; Animals; Anti-Inflammatory Agents; Atrophic; Behavior; Biodistribution; Biological Assay; Biomedical Engineering; Blindness; Canis familiaris; Capital; Capsid; Cells; Cessation of life; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Communication; Contralateral; Cyclic GMP; DNA; Dose; Dose-Limiting; Drug Kinetics; Electrophysiology (science); Endotoxins; Environment; Evaluation; Eye; Feedback; Frequencies; Functional disorder; Funding; Gene Amplification; Genes; IL6 gene; Individual; Inflammation; Injections; Interleukin-10; Light; Lighting; Measures; Modeling; Mus; Mutation; Nonexudative age-related macular degeneration; Ophthalmology; Opsin; Patients; Performance; Pharmacologic Substance; Phase; Phase I Clinical Trials; Photoreceptors; Phototoxicity; Phototransduction; Plasma; Plasmids; Privatization; Process; Production; Proteins; RPE65 protein; Radial; Regenerative Medicine; Resolution; Retina; Retinal Degeneration; Retinal Dystrophy; Retinitis Pigmentosa; Running; Safety; Simian virus 40; Small Business Innovation Research Grant; Specificity; Statistical Data Interpretation; Structure of retinal pigment epithelium; System; Thinness; Time; Toxic effect; Transfection; Translating; Viral Vector; Virus; Vision; Vitreous humor; base; clinical translation; commercialization; cone-rod dystrophy; cytokine; efficacy evaluation; efficacy outcomes; follow-up; gene therapy; improved; intravitreal injection; light intensity; meetings; minimally invasive; mouse model; open label; operation; optogenetics; phase II trial; preclinical study; response; retinal damage; retinal prosthesis; safety outcomes; sex; sight restoration; success; vector; water maze

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.

干性年龄相关性黄斑变性 (dry-AMD) 等视网膜变性会导致严重视力丧失 其中视网膜细胞发生功能障碍，导致视觉转导周期受阻。视网膜 假肢提供了恢复有限视力的可能性。然而，当前的系统受到较差的限制 分辨率，随着时间的推移视网膜损伤。视网膜细胞的光遗传学敏化具有作为临时方法的潜力 解决方案，直到再生医学成功。除了更高的分辨率之外，光遗传学还具有 具有细胞特异性、微创玻璃体内注射等优点。随着 Ambient-的出现 光激活、快速和宽带多特征视蛋白（MCO），临床转化的障碍 光遗传学视力恢复被移除。 II 期 SBIR 支持使我们能够完成严格的 支持 IND 的临床前研究，包括功效、药代动力学和 GLP 毒性的评估以及 玻璃体内注射 vMCO 在小型和大型动物中的生物分布。这些研究以投入为指导 FDA 在我们的 IND 前会议和后续沟通期间提供的信息。我们的 II 期 SBIR 研究表明 工艺开发的 vMCO 在超过 1 年的时间内保持稳定和有效，从而在 双极细胞。 MCO 剂量依赖性表达与视觉引导行为的改善高度相关 径向水迷宫和环境光照明下的光运动反应。此外，我们发现玻璃体内 注射 vMCO 驱动两种不同视网膜变性小鼠模型双极细胞中 MCO 的表达 和大型动物。 vMCO 在小鼠中的安全性通过在实验后未检测到的视网膜光毒性得到证实。 长期暴露在强光下四个月。此外，赞成和反对没有显着增加 注射 vMCO 六个月后，观察到血浆或玻璃体液中的炎症细胞因子。基于 这一成功和 FDA 的反馈，我们的目标是进一步开发用于恢复干眼症患者视力的产品 (vMCO) 在环境光环境下患有视网膜营养不良的 AMD 受试者。 IIb SBIR 阶段的目标 项目将通过三个目标来实现。目标 1：高产量的 vMCO 鲁棒受控生产 和可比较的性能；目标 2：使用评估转导功效和视觉功能 NHP 干 AMD 模型中的电生理学；目标 3：第一阶段开放标签剂量递增研究 评估晚期干性 AMD 患者眼内注射 vMCO 的安全性和耐受性。这 协作努力汇集互补的专业知识来解决视网膜的挑战性问题 退行性疾病。在 IIb SBIR 阶段完成后，我们预计将推进： (i) 启动阶段 - 2 评估功效的试验，以及 (ii) 加强我们与私募股权/风险投资公司的合作伙伴关系 制药公司进行商业化。该提案的成功将带来新的临床方法 用于在环境光下治疗干性 AMD 患者。这种与基因无关的方法将允许治疗其他疾病 视网膜退行性疾病，例如色素性视网膜炎、Stargardt 和视锥细胞营养不良。