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

由于年龄相关性黄斑变性（AMD）而发生严重的视力丧失， 美国人患有某种形式的AMD，预计到2050年将翻一番。目前临床上大多数 治疗主要集中在减缓疾病的进展，因为既没有治愈方法， 除了视网膜假体之外，也没有一种治疗方法可以恢复由于视网膜病变而丧失的视力。 退化然而，当前系统受限于差的分辨率（需要较高的电极密度）。 更多的电流，导致产热），视网膜损伤随着时间的推移和细胞过度生长，由于 外科植入视网膜细胞的光遗传致敏具有作为过渡解决方案的潜力， 再生医学是成功的。除了更高的分辨率外，光遗传学还具有比 例如细胞特异性的电刺激，并且不需要眼内手术。但临床 光遗传学使能的视力恢复的翻译具有需要活性药物的缺点， 由强度比环境光高一个数量级的光源刺激。降低该等 Nanoscope Technologies及其合作者开发了一种新型病毒载体， 特征性视蛋白（vMCO）对变性干性AMD视网膜中的视网膜细胞致敏。我们的电生理 研究表明，MCO敏化的视网膜可被环境光照射激活。此外，我们发现 ON双极细胞中的MCO表达在rd 10小鼠中持续至少16周，导致显著改善 在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： 慢性光暴露后的光毒性，没有可检测到的眼损伤，非感染性疾病中的最小量载体 靶器官，血浆中促炎细胞因子和抗炎细胞因子未增加，视网膜中无免疫细胞 注射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）用于在周围光环境中恢复患有视网膜营养不良的受试者的视力。的目标 本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在干燥环境中的安全性- AMD小鼠模型;目的2：在周围光环境中评价vMCO使能的长期视力恢复 在两种不同的小鼠模型（RD 1和RD 10）和RCD 1狗中使用行为测定和电生理学 目的3：野生型犬中玻璃体内注射vMCO的毒性和生物分布的GLP研究。 这种合作努力汇集了互补的专业知识，以解决视网膜病变中的一个具有挑战性的问题。 退化性疾病在第II阶段SBIR完成后，我们设想推进：（i）进一步的vMCO 产品开发，（ii）IIb期非人灵长类动物的疗效/安全性研究，（iii）IND申请 提交给FDA，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- AMD在环境光环境下。

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.