Neuroprotective Properties of a Novel Glaucoma Drug and Formulation

新型青光眼药物和制剂的神经保护特性

• 批准号: 10254556
• 负责人: Dianna Ammons Johnson
• 金额: $ 35.65万
• 依托单位: OCULO THERAPY, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254556
• 关键词: Address; Adult; Affect; Animal Model; Anterior; Axon; Binding; Blindness; Calcium; Calcium Channel; Cell Death; Cessation of life; Ciliary Body; Data; Disease; Dose; Drug Formulations; Drug Targeting; Engineering; Exhibits; Eye; Eyedrops; FDA approved; Formulation; Functional disorder; Funding; Glaucoma; Goals; Grant; Health; Hour; Lead; Longevity; Movement; Nerve Fibers; Neurons; Neuroprotective Agents; Optic Nerve; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Play; Pre-Clinical Model; Property; Research; Retina; Retinal Ganglion Cells; Risk Factors; Role; Site; Small Business Innovation Research Grant; Structure; System; Testing; Therapeutic; Topical application; United States; United States National Institutes of Health; Vision; Visual; Visual Fields; anterior chamber; base; design; druggable target; experience; genetic approach; high intraocular pressure; improved; innovation; meetings; nerve damage; neuroprotection; novel; phase 1 study; pregabalin; preservation; prevent; standard of care; treatment strategy; voltage

Glaucoma, the leading cause of irreversible blindness in the world; currently affects more than 3 million in the U.S. and is projected to increase to ~6.3 million by 2050. The four major types of adult-onset glaucoma all lead to vision loss through a final common pathway of retinal ganglion cell (RGC) dysfunction and/or death. The current standard of care includes treatment with IOP-lowering eye drops, all of which have limited efficacy. Specifically, IOP reduction does not fully prevent RGC death and resulting visual field loss in many glaucoma patients. In our previous NIH-funded studies, we identified both a novel IOP-lowering drug target, the calcium channel, voltage-dependent, α2δ1subunit (aka CACNA2D1) and a selective CACNA2D1 blocker, pregabalin (PRG), that lowers IOP. Lastly, we developed a topical extended release PRG microemulsion (ME) that increases drug entry into the eye, resulting in higher efficacy and duration of action. Our most recent studies have uncovered an unanticipated additional treatment benefit of PRG, namely its additional localization to, and neuroprotection of, RGCs and optic nerve (ON) as we have demonstrated in an animal model of normal tension glaucoma. Thus, PRG ME could be the first glaucoma therapy to both lower IOP and have direct, neuroprotective effects on RGCs and their axons. This current SBIR Phase I application is designed to validate our new findings regarding the neuroprotective effects of our PRG ME, and to establish its mechanism of action. Our central hypothesis is that our PRG ME will lower IOP with improved efficacy, as well as maintain the health of RGCs, a field of use for which there is currently no FDA-approved drug. This hypothesis is supported by our data showing that CACNA2D1 is located in RGCs and ON and that topical administration of our extended-release bioadhesive ME promotes delivery of PRG to the retina. Overall strengths of this project include: 1) a strong and experienced interdisciplinary OculoTherapy team; 2) engineering of an innovative delivery strategy using an extended-release formulation; 3) the use of a highly promising FDA-approved drug that will be repurposed as a glaucoma therapeutic; and 4) the discovery that the drug may have multiple sites of action within the eye that collectively provide IOP lowering through direct interactions with the ciliary body and/or outflow structures as well as direct RGC neuroprotection that is independent of its IOP-lowering capability. In this Phase I SBIR proposal, we will provide proof of concept and address key feasibility questions by establishing neuroprotective efficacy and mechanism of action of our PRG ME. This treatment strategy will reduce the burden to the patient and lead to better visual outcomes for glaucoma patients. To address our objective, we propose the following Aims: Aim 1: We test the hypothesis that PRG is a neuroprotectant for RGCs and the ON using once daily dosing. Aim 2: We test the hypothesis that PRG plays a direct role in RGC health by regulating the concentration of intracellular calcium (Ca2+).

青光眼是世界上导致不可逆转失明的主要原因；目前影响超过 300 万人； 美国，预计到 2050 年将增加到约 630 万。四种主要类型的成人发病青光眼均导致 通过视网膜神经节细胞（RGC）功能障碍和/或死亡的最终共同途径导致视力丧失。 目前的护理标准包括使用降低眼压的滴眼液进行治疗，但所有这些方法的疗效都很有限。 具体来说，降低眼压并不能完全防止许多青光眼患者的 RGC 死亡和由此导致的视野丧失 在我们之前由 NIH 资助的研究中，我们发现了一种新的降低眼压的药物靶点，即钙。 电压依赖性通道 α2δ1 亚基（又名 CACNA2D1）和选择性 CACNA2D1 阻断剂， 普瑞巴林 (PRG)，可降低眼压 最后，我们开发了一种局部缓释 PRG 微乳剂 (ME)。 增加药物进入眼睛，从而提高疗效和作用持续时间。 研究发现 PRG 具有意想不到的额外治疗益处，即其额外的定位 正如我们在正常动物模型中所证明的那样，对 RGC 和视神经 (ON) 具有神经保护作用 因此，PRG ME 可能是第一种既能降低眼压又能直接治疗青光眼的疗法。 目前的 SBIR I 期应用旨在对 RGC 及其轴突产生神经保护作用。 验证我们关于 PRG ME 神经保护作用的新发现，并建立其机制 我们的中心假设是，我们的 PRG ME 将降低 IOP，提高疗效，并维持疗效。 RGC 的健康，目前尚无 FDA 批准的药物。 我们的数据支持显示 CACNA2D1 位于 RGC 和 ON，并且局部给药 我们的缓释生物粘附剂 ME 促进 PRG 向视网膜的输送 该项目的整体优势。 包括：1) 强大且经验丰富的跨学科眼科治疗团队；2) 创新工程； 使用缓释制剂的递送策略；3) 使用 FDA 批准的非常有前途的药物 将被重新用作青光眼治疗剂；4）发现该药物可能具有多个位点 通过与睫状体的直接相互作用共同降低眼压的眼内作用 和/或流出结构以及独立于其 IOP 降低的直接 RGC 神经保护 在第一阶段 SBIR 提案中，我们将提供概念验证并解决关键的可行性问题。 通过建立我们的 PRG ME 这种治疗策略的神经保护功效和作用机制。 减轻患者的负担并为青光眼患者带来更好的视力结果。 目标，我们提出以下目标： 目标 1：我们检验 PRG 是神经保护剂的假设 RGC 和 ON 每日一次给药 目标 2：我们检验 PRG 在 RGC 中发挥直接作用的假设。 通过调节细胞内钙（Ca2+）的浓度来维持健康。