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: 9912475
• 负责人: MONICA M JABLONSKI
• 金额: $ 113.77万
• 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/9912475
• 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; 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; 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; genetic profiling; high intraocular pressure; individualized medicine; inhibitor/antagonist; innovation; 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.

青光眼是世界上不可逆失明的主要原因。眼内压（IOP）是 导致残留神经节细胞死亡（RGC）死亡的最重要的危险因素，并导致视野丧失 初级开角素（POAG）。青光眼目前的护理标准包括使用IOP- 降低药物随着眼部滴的局部输送。但是，许多患者继续失去视野 尽管正在下降。我们采取了一种全面的遗传学方法来寻求新药 可能解决当前疗法局限性的目标。我们已经证明了cacna2d1是 专门与小鼠和人类的高IOP相关。我们还表明了选择性cacna2d1 阻止器表现出潜在的降低IOP的活动，可以达到最大降低IOP> 40％ 通过生物粘附微乳液交付时，返回基线约33小时。我们还确定 CACNA2D1位于CB，TM和RGC，表明该蛋白的抑制剂都可以降低 IOP并保护RGC。最后，我们表明降低的IOP降低程度与基因相关 单倍型，因此证明了针对患者的遗传特征调整治疗的潜力。我们的整体 目的是开发和验证一种或多种新型局部配方，以将有效药物提供给 抑制每天局部局部配方中的cacna2d1。这种治疗策略将减少燃烧 患者，提高依从性并导致更好的视觉结果。我们的中心假设是一个小的 靶向cacna2d1的分子（在局部微乳液中配制时）将引起降低IOP的 与其他青光眼药物相比，放大器和持续时间更大的反应。总体优势 建议包括：1）强大的跨学科团队的组合； 2）成功利用 遗传学方法确定了阻断IOP和RGC的青光眼相关增加的新药物靶标 死亡; 3）将我们的新药物用于精确医学的潜力； 4）发展和 使用扩展释放公式优化创新的IOP交付策略。在这个建议中，我们 通过建立效率，提供概念证明数据并解决关键可行性问题， 我们新型微乳液处理的药效学，生物相容性和生物分布。我们开发一个 每天的新局部局部微乳液配方作为一种新的青光眼疗法；测量 CACNA2D1跨角膜的抑制剂，确定眼睛中的药代动力学运动，并全面评估 身体生物分布；建立CACNA2D1抑制剂作为青光眼疗法的作用机理； 确定CACNA2D1的单倍型是否影响对我们公式的降低反应；和 准备并向FDA提交IND申请。这些结果将使我们直接进入一个阶段 II示范项目为第三阶段的商业化做准备。