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: 10597097
• 负责人: MONICA M JABLONSKI
• 金额: $ 93.9万
• 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/10597097
• 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; Emulsions; Engineering; Exhibits; Eye; Eyedrops; Formulation; Genes; Genetic; Glaucoma; Goals; Haplotypes; Hour; Human; Hyperemia; Incidence; Investigational New Drug Application; Link; Macaca; Marketing; Measurement; Measures; 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; R24; 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

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.

青光眼是世界上不可逆性失明的主要原因。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风险因素 原发性开角型青光眼（POAG）。目前青光眼的护理标准包括用IOP治疗， 降低作为眼药水的局部给药。然而，许多患者继续失去视野 尽管在使用降眼压的药物我们采取了综合性的遗传学方法来寻找新药 这些目标可能解决当前疗法的局限性。我们已经证明了Cacna 2d 1是 与小鼠和人类的高IOP有特异性联系。我们还表明，选择性Cacna 2d 1 阻滞剂具有强效的降眼压活性，可实现最大IOP降低>40%， 当通过生物粘附性微乳液递送时，恢复至基线约33小时。我们还确定， CACNA 2D 1定位于CB、TM和RGCs，这表明该蛋白的抑制剂可以降低 IOP和保护RGC。最后，我们已经表明，眼压降低的程度与基因相关， 单倍型，从而证明了定制治疗患者的遗传概况的潜力。我们的整体 目的是开发和验证一种或多种新的局部制剂， 抑制CACNA 2D 1，每日一次局部制剂。这种治疗策略将减轻患者的负担。 患者，增加依从性，并导致更好的视觉效果。我们的核心假设是， 靶向CACNA 2D 1的分子-当配制成局部微乳剂时-将引起IOP降低 反应的幅度和持续时间比其他青光眼药物更大。这一点的总体优势 建议包括：1）强大的跨学科团队的结合; 2）成功利用 用遗传学方法鉴定阻断青光眼相关IOP和RGC增加的新药靶点 死亡; 3）利用我们的新药进行精准医疗的潜力; 4）开发和 使用缓释制剂优化创新性IOP递送策略。在本提案中，我们 提供概念验证数据，并通过建立有效性解决关键可行性问题， 药效学、生物相容性和生物分布。我们开发了一个 一种新的局部每日一次微乳制剂作为新的青光眼治疗;测量 CACNA 2D 1抑制剂穿过角膜，确定眼内的药代动力学运动，并评估全 身体生物分布;建立CACNA 2D 1抑制剂作为青光眼治疗的作用机制; 确定Cacna 2d 1的单倍型是否影响对我们的制剂的IOP降低反应;以及 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 第二阶段示范项目，为第三阶段商业化做准备。