Mitochondrial-Targeted Therapy for Macular Degeneration

线粒体靶向治疗黄斑变性

• 批准号: 10602150
• 负责人: Scott William Cousins
• 金额: $ 75万
• 依托单位: ECLIPSE LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602150
• 关键词: Address; Affect; Age related macular degeneration; Alcohols; Applications Grants; Atrophic; Biochemical; Biological Availability; Biological Response Modifier Therapy; Biological Sciences; Blindness; Bolus Infusion; Cells; Clinical Research; Clinical Trials; Deposition; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug Targeting; Drusen; Dryness; Elderly; Esters; Eye; Fatty acid glycerol esters; Formulation; Goals; Good Manufacturing Process; Growth; In Vitro; Injections; Investigational Drugs; Lead; Link; Lipids; Macular degeneration; Mitochondria; Modeling; Modification; Nonexudative age-related macular degeneration; Organelles; Oryctolagus cuniculus; Patients; Penetration; Pharmaceutical Preparations; Phase; Photoreceptors; Pigment Epithelium; Pre-Clinical Model; Preparation; Prodrugs; Production; Proteins; Reading; Research; Retina; Schedule; Small Business Innovation Research Grant; Specific qualifier value; Superoxides; Therapeutic; Time; Tissues; Toxicology; Vision; Visual Acuity; advanced disease; design; effective therapy; efficacy study; geographic atrophy; good laboratory practice; improved; in vivo; in vivo Model; intravitreal injection; luminance; manufacture; mitochondrial dysfunction; novel; novel therapeutics; off-patent; open label; polyarginine; pre-Investigational New Drug meeting; pre-clinical; repaired; response; small molecule; subcutaneous; targeted treatment; Address; Affect; Age related macular degeneration; Alcohols; Applications Grants; Atrophic; Biochemical; Biological Availability; Biological Response Modifier Therapy; Biological Sciences; Blindness; Bolus Infusion; Cells; Clinical Research; Clinical Trials; Deposition; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug Targeting; Drusen; Dryness; Elderly; Esters; Eye; Fatty acid glycerol esters; Formulation; Goals; Good Manufacturing Process; Growth; In Vitro; Injections; Investigational Drugs; Lead; Link; Lipids; Macular degeneration; Mitochondria; Modeling; Modification; Nonexudative age-related macular degeneration; Organelles; Oryctolagus cuniculus; Patients; Penetration; Pharmaceutical Preparations; Phase; Photoreceptors; Pigment Epithelium; Pre-Clinical Model; Preparation; Prodrugs; Production; Proteins; Reading; Research; Retina; Schedule; Small Business Innovation Research Grant; Specific qualifier value; Superoxides; Therapeutic; Time; Tissues; Toxicology; Vision; Visual Acuity; advanced disease; design; effective therapy; efficacy study; geographic atrophy; good laboratory practice; improved; in vivo; in vivo Model; intravitreal injection; luminance; manufacture; mitochondrial dysfunction; novel; novel therapeutics; off-patent; open label; polyarginine; pre-Investigational New Drug meeting; pre-clinical; repaired; response; small molecule; subcutaneous; targeted treatment

SUMMARY Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. Most AMD cases are the nonexudative (or “dry”) form, which affects up to 200 million patients globally and is comprised of intermediate dry AMD, characterized by formation of sub-retinal pigment epithelium (RPE) deposits called drusen, and geographic atrophy (GA), more advanced disease characterized by loss of RPE and photoreceptors. Currently, there are no available treatments for any form of dry AMD. Thus, there is a tremendous unmet need for any effective therapy. Mitochondrial dysfunction at the RPE has been established as a major disease mechanism for dry AMD. While systemically administered mitochondria-targeted drugs have shown promise in preclinical and early-phase clinical studies of dry AMD, they have limitations, including insufficient bioavailability at the retina in some patients. The purpose of this Direct to Phase 2 SBIR grant application is to develop a novel intravitreal extended release mitochondria targeted drug (IVT Mito XR) for the treatment of dry AMD. Eclipse Life Sciences has designed novel mitochondria targeted prodrugs of EY005 (lead and backups). Preliminary studies demonstrate that the lead EY005 prodrug and a pilot formulation of the prodrug in IVT Mito XR has excellent efficacy in both in vitro and in vivo models of mitochondrial dysfunction that are relevant to dry AMD. The proposed project is focused on developing lead and backup formulations of IVT Mito XR using Eclipse’s proprietary extended release drug delivery system (XRDDS), to achieve target product specification of 3 months’ sustained release of EY005 following a single intravitreal injection. Aim 1 will finalize IVT Mito XR formulations of lead and backup prodrugs. Aim 2 will be to perform nonGLP (good laboratory practice) pharmacokinetics, toxicology, and proof of concept efficacy studies of IVT Mito XR in rabbit models. Aim 3 will be to execute GMP (good manufacturing practice) production and preliminary characterization of lead EY005 prodrug. The end deliverable will be submission of a pre-IND package in preparation for scheduling a pre-IND meeting with FDA.

概括 与年龄相关的黄斑变性（AMD）是老年失明的最常见原因。大多数 案例是非X例（或“干”）形式，全球影响多达2亿名患者，并且已完成 中间干AMD，其特征是形成视网膜色素上皮（RPE）沉积物称为 德鲁森和地理萎缩（GA），以RPE和RPE丧失为特征 感受器。目前，对于任何形式的干amd都没有可用的治疗方法。那有一个 对任何有效疗法的巨大不满意。 RPE的线粒体功能障碍已建立 作为干燥AMD的主要疾病机制。虽然系统地施用线粒体靶向药物 已经在干燥AMD的临床前和早期临床研究中表现出了希望，它们具有局限性，包括 某些患者的视网膜生物利用度不足。直接到第二阶段SBIR赠款的目的 应用是为玻璃体内扩展释放线粒体靶向药物（IVT mito XR）的应用 干燥AMD的处理。 Eclipse Life Sciences设计了新型的线粒体针对EY5的前药 （铅和备份）。初步研究表明，EY5前药和试点公式 IVT MITO XR的前药在线粒体功能障碍的体外和体内模型中均具有出色的效率 与干燥的AMD有关。拟议项目的重点是开发铅和备份公式 使用Eclipse的专有扩展释放药物输送系统（XRDDS），IVT Mito XR以实现目标 单次注射后3个月持续释放EY005的产品规范。目标1意志 最终确定铅和备用前药的IVT Mito XR公式。 AIM 2将是执行nonglp（好 实验室实践）药代动力学，毒理学和IVT mito XR概念有效性研究证明 兔子模型。 AIM 3将是执行GMP（良好的制造实践）生产和初步 铅EY5前药的表征。结束交付将是提交预先指示的包裹 准备安排与FDA的预定会议的准备。