Novel Extended Release Glaucoma Therapy for Once Daily Dosing

每日一次给药的新型青光眼缓释疗法

• 批准号: 10374760
• 负责人: MONICA M JABLONSKI
• 金额: $ 92.71万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374760
• 关键词: Address; Advanced Development; Affect; American; Aqueous Humor; Biodistribution; Blindness; Calcium Channel; Cell Death; Cessation of life; Characteristics; Ciliary Body; Clinical Trials; Cornea; Data; Development; Disease; Dose; Drainage procedure; Drops; Drug Compounding; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug usage; Engineering; Exhibits; Eye; Eyedrops; Formulation; Genes; Genetic; Glaucoma; Goals; Haplotypes; Hour; Human; Hyperemia; Incidence; Investigational New Drug Application; Lead; Link; Macaca; Measurement; Measures; Monoclonal Antibody R24; Movement; Mus; Optic Nerve; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Penetration; Performance; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiologic Intraocular Pressure; Positioning Attribute; Preparation; Primary Open Angle Glaucoma; Production; Proteins; Research; Research Personnel; Retinal Ganglion Cells; Risk Factors; Time; Topical application; Trabecular meshwork structure; United States; Visual; Visual Fields; aqueous humor flow; biomaterial compatibility; chemical synthesis; commercialization; compliance behavior; endophenotype; experience; experimental study; genetic approach; high intraocular pressure; individualized medicine; inhibitor; innovation; nerve damage; neuroprotection; new therapeutic target; novel; novel therapeutics; personalized approach; precision medicine; pregabalin; residence; response; retinal axon; side effect; small molecule; small molecule inhibitor; standard of care; treatment strategy; voltage

Glaucoma is the leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is the most significant risk factor contributing to death of retinal ganglion cells (RGCs) and resulting visual field loss in primary open angle glaucoma (POAG). The current standard of care for glaucoma includes treatment with IOP- lowering medications delivered topically as eye drops. However, many patients continue to lose visual fields despite being on IOP-lowering drops. We have taken a comprehensive genetics approach to seek new drug targets that may address the limitations of current therapies. We have demonstrated that Cacna2d1 is specifically linked to high IOP both in mice and humans. We have also shown that a selective Cacna2d1 blocker exhibits potent IOP-lowering activity that can achieve a maximal IOP reduction >40% that does not return to baseline for ~33 hours when delivered by bioadhesive microemulsion. We have also determined that CACNA2D1 is localized to the CB, TM and RGCs, suggesting that inhibitors of this protein could both lower IOP and protect RGCs. Lastly, we have shown that the degree of IOP lowering is correlated with the gene haplotype, thus demonstrating the potential of tailoring treatment to a patient’s genetic profile. Our overall objective is to develop and validate one or more novel topical formulations to deliver the effective drugs to inhibit CACNA2D1 in a once daily topical formulation. This treatment strategy will reduce the burden to the patient, increase compliance and lead to better visual outcomes. Our central hypothesis is that a small molecule that targets CACNA2D1—when formulated in a topical microemulsion—will elicit an IOP-lowering response that is greater in amplitude and duration than other glaucoma medications. Overall strengths of this proposal include: 1) the combination of a strong interdisciplinary team; 2) the successful utilization of a genetics approach to identify a new drug target for blocking glaucoma-related increases in IOP and RGC death; 3) the potential for utilizing our novel drug for precision medicine and; 4) the development and optimization of an innovative IOP delivery strategy using an extended-release formulation. In this proposal, we provide proof-of-concept data and address key feasibility questions by establishing efficacy, pharmacodynamics, biocompatibility and biodistribution of our novel microemulsion treatment. We develop a novel topical once daily microemulsion formulation as a new glaucoma therapy; measure the movement of CACNA2D1 inhibitors across the cornea, determine pharmacokinetic movements in the eye and assess full- body biodistribution; establish the mechanism of action of CACNA2D1 inhibitors as glaucoma therapies; determine if the haplotype of Cacna2d1 influences the IOP-lowering response to our formulation(s); and prepare and submit an IND application to the FDA. These results will position us to proceed directly to a Phase II demonstration project in preparation for Phase III commercialization.

青光眼是世界上导致不可逆转失明的主要原因。眼内压（IOP）升高是 导致视网膜神经节细胞（RGC）死亡并导致视野丧失的最重要的危险因素 原发性开角型青光眼（POAG）。目前青光眼的护理标准包括 IOP- 降低以滴眼剂形式局部给药的药物。然而，许多患者继续丧失视野 尽管正在服用降低眼压的药物。我们采取了全面的遗传学方法来寻找新药 可能解决当前疗法局限性的目标。我们已经证明 Cacna2d1 是 与小鼠和人类的高眼压特别相关。我们还证明了选择性 Cacna2d1 阻滞剂表现出有效的 IOP 降低活性，可实现最大 IOP 降低 >40% 当通过生物粘附微乳液递送时，约 33 小时即可恢复到基线。我们还确定 CACNA2D1 定位于 CB、TM 和 RGC，表明该蛋白的抑制剂可以降低 IOP 并保护 RGC。最后，我们发现眼压降低的程度与基因相关 单倍型，从而证明了根据患者的基因谱定制治疗的潜力。我们的整体 目标是开发和验证一种或多种新颖的局部制剂，以将有效的药物传递给 每日一次的局部制剂可抑制 CACNA2D1。这一治疗策略将减轻患者的负担 患者，提高依从性并带来更好的视觉效果。我们的中心假设是一个小 当以局部微乳液形式配制时，靶向 CACNA2D1 的分子将引起眼压降低 与其他青光眼药物相比，反应的幅度和持续时间更大。本次综合实力 建议包括： 1） 组合一个强大的跨学科团队； 2) 成功利用 遗传学方法确定新的药物靶点，以阻止青光眼相关的 IOP 和 RGC 增加 死亡; 3）利用我们的新药进行精准医疗的潜力； 4）发展与 使用缓释制剂优化创新的 IOP 输送策略。在这个提案中，我们 提供概念验证数据并通过确定功效来解决关键的可行性问题， 我们的新型微乳治疗的药效学、生物相容性和生物分布。我们开发了一个 作为一种新的青光眼疗法的新型外用每日一次微乳制剂；测量运动 CACNA2D1 抑制剂穿过角膜，确定眼睛中的药代动力学运动并评估全面 体内生物分布；建立 CACNA2D1 抑制剂治疗青光眼的作用机制； 确定 Cacna2d1 的单倍型是否影响我们的配方的 IOP 降低反应；和 准备并向 FDA 提交 IND 申请。这些结果将使我们能够直接进入一个阶段 二期示范项目正在为三期商业化做准备。