AMBIENT LIGHT ACTIVATABLE OPSIN BASED THERAPY FOR AGE-RELATED MACULAR DEGENERATION

年龄相关性黄斑变性(AMD)导致严重视力丧失，约1500万人 美国人患有某种形式的AMD，预计到2050年将翻一番。目前临床上的大多数 治疗主要集中在减缓疾病的进展上，因为既没有治愈的方法 除了视网膜假体之外，也没有一种治疗方法可以恢复因以下原因而丧失的视力 堕落。然而，当前的系统受到低分辨率的限制(需要更高的电极密度 更多的电流，导致热产生)，一段时间内的视网膜损伤和细胞过度生长 外科植入术。视网膜细胞的光遗传敏化有可能作为一种临时解决方案，直到 再生医学是成功的。除了更高的分辨率外，光遗传学还具有 电刺激等细胞特异性强，不需要眼内手术。然而，临床上 光遗传使能视力恢复的翻译的缺点是需要主动的 光源的刺激，其强度比周围光线高一个数量级。为了缓解这些问题 问题，纳米技术公司及其合作者已经开发出一种新型的病毒载体，该载体携带多个 特异视蛋白(VMCO)可使变性干性AMD视网膜的视网膜细胞增敏。我们的电生理学 研究表明，MCO敏化的视网膜可以通过环境光照明激活。此外，我们发现， 在rd10小鼠中，双极细胞上的MCO表达持续至少16周，导致显著改善 在环境光水平下的视觉引导行为。VMCO在小鼠体内的安全性通过以下方式得到证实：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 靶器官，血浆中促炎症和抗炎细胞因子不增加，视网膜中没有免疫细胞 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)，用于在环境光环境中恢复视网膜营养不良患者的视力。的目标 该项目将通过：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；目标2：评估环境光环境下vMCO启用的长期视力恢复 两种不同小鼠模型(RD1和RD10)和RCD1犬的行为学和电生理学研究 目的3：玻璃体内注射vMCO的毒性和生物分布的GLP研究。 这一合作努力将互补的专业知识聚集在一起，以解决视网膜中的一个具有挑战性的问题 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，(2)在非人类灵长类动物中的功效/安全性研究，通过第二阶段b，(3)IND应用 提交给FDA，以及(Iv)与风险投资和制药公司合作 商业化。这项建议的成功将导致一种新的临床方法来治疗干燥症患者。 环境光环境下的AMD。

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.