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: 9789322
• 负责人: Samarendra Kumar Mohanty
• 金额: $ 95.04万
• 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/9789322
• 关键词: Accounting; Address; Age; Age related macular degeneration; Anti-inflammatory; Antibodies; Behavior; Behavioral; Behavioral Assay; Biodistribution; Biological Assay; Biology; Biomedical Engineering; Biometry; Blindness; Blood; Canis familiaris; Capital; Capsid; Caspase; Cells; Characteristics; Chronic; Clinical; Clinical Pathology; Clinical Treatment; Confocal Microscopy; DNA; DNA analysis; Diagnosis; Disease Progression; Dose; Dose-Limiting; Elderly; Electric Stimulation; Electrodes; Electrophysiology (science); Environment; Enzyme-Linked Immunosorbent Assay; Eye; FDA approved; Feedback; Guidelines; Head Movements; Histopathology; Immune; Immunohistochemistry; Individual; Injections; Light; Lighting; Macular degeneration; Measurement; Measures; Modeling; Mus; Neurosciences; Operative Surgical Procedures; Ophthalmology; Opsin; Optokinetic nystagmus; Organ; PTPRC gene; Patients; Peripheral Blood Mononuclear Cell; Pharmacologic Substance; Phase; Photic Stimulation; Photophobia; Photoreceptors; Phototoxicity; Plasma; Prevalence; Production; Proteins; Radial; Regenerative Medicine; Residual state; Resolution; Retina; Retinal; Retinal Degeneration; Retinal Dystrophy; Safety; Sampling; Signal Transduction; Small Business Innovation Research Grant; Source; Specificity; Structure; System; Technology; Therapeutic; Therapeutic Effect; Thermogenesis; Time; Toxic effect; Toxicology; Transgenes; Viral Vector; Vision; Visual Cortex; Visual Perception; arm; base; clinical translation; commercialization; cytokine; density; efficacy study; implantation; in vivo; intravitreal injection; light intensity; macula; mouse model; nanoscope; nonhuman primate; novel; optogenetics; product development; response; restoration; retinal damage; retinal prosthesis; safety study; sex; success; systemic toxicity; therapeutic evaluation; vector; water maze

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.

由于年龄相关的黄斑变性（AMD）而发生严重的视力丧失，约1500万 美国的人们有某种形式的AMD，预计到2050年将翻一番。当前的大多数临床 治疗主要集中于降低疾病的进展，因为既没有治愈方法 除了视网膜假体以外，这可以阻止变性或疗法，从而恢复由于 变性。但是，当前系统受到分辨率差的限制（较高的电极密度需要 更多的电流，导致热量产生），一段时间内的视网膜损害以及由于 手术植入。视网膜细胞的光学遗传敏化具有潜力作为临时溶液，直到 再生医学成功。除了更高的分辨率外，光遗传学还优于 电刺激（例如细胞特异性），不需要眼内手术。但是，临床 启用光遗传学的视力恢复的翻译遭受了需要主动的缺点 光源的刺激强度比环境光高的数量级。减轻这些 问题，纳米镜技术及其合作者已经开发了一种新型的病毒载体 特征性的OPSIN（VMCO）使视网膜细胞在退化的干燥AMD视网膜中敏感。我们的电生理学 研究表明，通过环境光照明，MCO敏化的视网膜可以激活。此外，我们发现 在双极细胞上的MCO表达在RD10小鼠中持续至少16周，从而显着改善 在环境光级别的视觉指导行为。 VMCO在小鼠中的安全性通过：未检测到 慢性光暴露后的光毒性，未检测到的眼损伤，非 - 非载体数量最少 有针对性的器官，血浆中的PRO和抗炎细胞因子无增加，视网膜中没有免疫细胞 注射VMCO后。基于FDA的成功和反馈，我们旨在进一步开发产品 （VMCO）用于恢复环境光环境中视网膜营养不良的受试者的视力。目标的目标 该项目将通过：AIM 1：量化VMCO的长期稳定性以及VMCO在干燥中的安全性 AMD小鼠模型； AIM 2：在环境光环境中评估具有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; AIM 3：GLP研究野生型狗中注射玻璃体内注射VMCO的毒性和生物分布。 这种合作的努力汇集了互补的专业知识，以解决视网膜中一个具有挑战性的问题 退化性疾病。 II阶段SBIR完成后，我们将设想进步：（i）进一步的VMCO 产品开发，（ii）非人类灵长类动物通过IIB的功效/安全研究，（iii）IND应用 提交给FDA，（iv）与风险投资和制药公司合作 商业化。该提案的成功将导致一种新的临床方法，用于治疗干燥患者 AMD在环境光环境下。