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: 9975579
• 负责人: Samarendra Kumar Mohanty
• 金额: $ 7.76万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975579
• 关键词: Address; Age related macular degeneration; Anti-Inflammatory Agents; Behavior; Behavioral Assay; Biodistribution; Blindness; Canis familiaris; Capital; Cells; Characteristics; Chronic; Clinical; Clinical Treatment; Disease Progression; Electric Stimulation; Electrodes; Electrophysiology (science); Environment; Feedback; Immune; Individual; Injections; Light; Lighting; Modeling; Mus; Nonexudative age-related macular degeneration; Operative Surgical Procedures; Opsin; Organ; Patients; Pharmacologic Substance; Phase; Phototoxicity; Plasma; Regenerative Medicine; Resolution; Retina; Retinal Degeneration; Retinal Dystrophy; Safety; Small Business Innovation Research Grant; Source; Specificity; System; Technology; Thermogenesis; Time; Toxic effect; Viral Vector; Vision; base; clinical translation; commercialization; cytokine; density; implantation; intravitreal injection; mouse model; nanoscope; nonhuman primate; novel; optogenetics; product development; restoration; retinal damage; retinal prosthesis; safety study; success; vector

Severe loss of vision occurs due to age-related macular degeneration (AMD) and approximately 15 million people in the US have some form of AMD, which is expected to double by 2050. Most of the current clinical treatments are primarily focused on slowing down the progression of the disease, as there is neither a cure that can stop the degeneration nor a therapy, other than retinal prostheses, that can restore vision lost due to the degeneration. Current systems, however, are limited by poor resolution (higher electrode density requiring more current, leading to heat production), retinal damage over a time period and cellular overgrowth due to surgical implantation. 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 over electrical stimulation such as cellular specificity and does not require intraocular surgery. However, clinical translation of optogenetic enabled vision restoration suffers from the drawback of requiring an active stimulation by light source having intensity an order of magnitude higher than ambient light. To mitigate these problems, Nanoscope Technologies and its collaborators have developed a novel viral vector carried multi- characteristic opsin (vMCO) to sensitize retinal cells in degenerated dry-AMD retina. Our electrophysiology studies demonstrate that MCO sensitized retina is activatable by ambient light illumination. Further, we found that MCO expression in ON bipolar cells lasts at least 16 wks in rd10 mice, leading to significant improvement of visually guided behavior at ambient light level. The safety of vMCO in mice is confirmed by: no detectable phototoxicity after chronic light exposure, no detectable ocular damage, minimal quantities of vector in non- targeted organs, no increase of pro and anti-inflammatory cytokines in plasma, and no immune cells in retina after vMCO injection. Based on this success and feedback from FDA, we aim to further develop the product (vMCO) for restoring vision in subjects with retinal dystrophies in ambient light environment. The objectives of this project will be accomplished by: Aim 1: Quantify long-term stability of vMCO and safety of vMCO in dry- AMD mice model; Aim 2: Evaluate vMCO-enabled long-term vision restoration in ambient light environment using behavioral assays and electrophysiology in two different mice models (rd1 and rd10) and rcd1 dog model; and Aim 3: GLP Study of toxicity and biodistribution of intravitreally-injected vMCO in wild-type dogs. This collaborative effort brings together complementary expertise to address a challenging problem in retinal degenerative diseases. Upon completion of the Phase II SBIR we envision to advance: (i) further vMCO product development, (ii) efficacy/safety studies in non-human primate through Phase IIb, (iii) IND application submission to FDA, and (iv) partnering with venture capital 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 environment.

约 1500 万人因年龄相关性黄斑变性 (AMD) 导致视力严重丧失 在美国，患有某种形式 AMD 的人预计到 2050 年将增加一倍。目前的大多数临床治疗 治疗主要集中在减缓疾病的进展，因为没有治愈方法 除了视网膜假体之外，没有任何疗法可以阻止退化，也没有其他疗法可以恢复因视网膜退化而丧失的视力 退化。然而，当前的系统受到分辨率差的限制（需要更高的电极密度） 更多的电流，导致热量产生），一段时间内的视网膜损伤和细胞过度生长 手术植入。视网膜细胞的光遗传学敏化有潜力作为临时解决方案，直到 再生医学是成功的。除了分辨率更高之外，光遗传学还具有优于 电刺激如细胞特异性且不需要眼内手术。然而，临床 光遗传学翻译使视力恢复具有需要主动的缺点 强度比环境光高一个数量级的光源的刺激。为了减轻这些 Nanoscope Technologies 及其合作者开发了一种携带多种病毒的新型病毒载体 特征性视蛋白 (vMCO) 使退化的干性 AMD 视网膜中的视网膜细胞变得敏感。我们的电生理学 研究表明，MCO 敏化视网膜可通过环境光照射激活。进一步，我们发现 在 rd10 小鼠中，ON 双极细胞中的 MCO 表达持续至少 16 周，从而导致显着改善 环境光水平下的视觉引导行为。 vMCO 在小鼠中的安全性得到证实：未检测到 慢性光暴露后的光毒性，没有可检测到的眼部损伤，非光载体中的载体数量极少 靶器官，血浆中促炎细胞因子和抗炎细胞因子没有增加，视网膜中没有免疫细胞 注入VMCO后。基于这一成功和 FDA 的反馈，我们的目标是进一步开发该产品 （vMCO）用于在环境光环境下恢复视网膜营养不良受试者的视力。的目标 该项目将通过以下方式完成： 目标 1：量化 vMCO 的长期稳定性和 vMCO 在干环境中的安全性 AMD小鼠模型；目标 2：评估环境光环境中支持 vMCO 的长期视力恢复 在两种不同的小鼠模型（rd1 和 rd10）和 rcd1 狗中使用行为测定和电生理学 模型;目标 3：玻璃体内注射 vMCO 在野生型犬中的毒性和生物分布的 GLP 研究。 这种协作努力汇集了互补的专业知识，以解决视网膜的挑战性问题 退行性疾病。在第二阶段 SBIR 完成后，我们预计将推进：(i) 进一步的 vMCO 产品开发，(ii) 通过 IIb 期在非人类灵长类动物中进行功效/安全性研究，(iii) IND 申请 向 FDA 提交申请，以及 (iv) 与风险投资和制药公司合作 商业化。该提案的成功将为治疗干咳患者带来新的临床方法。 AMD 在环境光环境下。