New Treatments for Glaucoma

青光眼的新治疗方法

基本信息

批准号：
10325637
负责人：
Sanket Mishra
金额：
$ 34.66万
依托单位：
GRANNUS THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325637
关键词：
Address Adolescent Adrenergic beta-Antagonists Adverse effects Affinity American Animal Model Animals Aqueous Humor Binding Biological Biological Assay Blindness Cardiotoxicity Cell Death Cell model Cells Chemicals Clinical Clinical Research Clinical Trials Crystallization Data Development Disease Drug Design Effectiveness Endoplasmic Reticulum Evaluation Exhibits Extracellular Matrix Eye Eyedrops Face Florida Formulation Functional disorder Funding Gene Silencing Glaucoma Goals Health Human In Vitro Inherited Investigational Drugs Lead Measurement Measures Molecular Chaperones Molecular Conformation Mus Mutate Mutation Open-Angle Glaucoma Optic Nerve Patients Persons Pharmaceutical Preparations Pharmacology Phase Phenotype Physiologic Intraocular Pressure Primary Open Angle Glaucoma Property Protein Isoforms Proteins Regimen Research Retinal Ganglion Cells Safety Secure Series Small Business Innovation Research Grant Small Business Technology Transfer Research Steroids Structure Structure-Activity Relationship Synthetic Prostaglandins System Testing Therapeutic Therapeutic Agents Topical application Toxicology Trabecular meshwork structure Triage Universities Vision Work analog antiglaucoma drug base clinical candidate cytotoxicity demographics design drug candidate efficacy study experimental study functional group gain of function glucose-regulated protein 94 improved in vitro Model in vivo inhibitor/antagonist innovation lead optimization mutant myocilin nerve damage novel pharmacokinetics and pharmacodynamics phase 2 study preclinical evaluation preclinical study prevent protein aggregation research clinical testing safety study safety testing scaffold small molecule symptom treatment therapeutically effective translational study

项目摘要

Abstract Aggregation of mutated myocilin (MYOC), a protein found in the endoplasmic reticulum (ER) of trabecular meshwork (TM) cells, disrupts the outflow of aqueous humor from the eye, causing increase in intraocular pressure (IOP), progressive retinal ganglion cell (RGC) death, and degeneration of the optic nerve, leading to primary open-angle glaucoma (POAG), characterized by irreversible vision loss. About 5% of POAG and 35 % of juvenile open-angle glaucoma (JOAG) patients exhibit glaucoma that is driven by the aggregation of mutant forms of MYOC. Our research team identified the endoplasmic reticulum (ER)-residing Hsp90 isoform, glucose- regulated protein 94 (Grp94), as necessary for the assembly of mutant myocilin aggregates. In fact, our group demonstrated that Grp94 inhibitors are effective in vivo to treat this hereditary glaucoma. Interestingly, Grp94 inhibition also prevents the IOP driven by steroids; a condition that leads to a secondary steroid-induced glaucoma (SIG). These data suggest that Grp94 inhibitors have the potential to treat any open-angle glaucoma. Current glaucoma treatments, such as beta blockers and prostaglandin analogs, only treat the symptoms of the disease and not the underlying cause. Our approach through Grp94 inhibition, represents a unique opportunity to treat mutant MYOC-driven POAG and allow persons afflicted with SIG to maintain their steroid regimens without sacrificing their vision. This application aims to secure funds for the optimization of Grp94 inhibitors to improve selectivity, modulation of physicochemical properties that are appropriate for ocular administration, and conduct pre-clinical evaluation of the optimized candidates in animal models. Preliminary work at the University of Notre Dame and the University of Florida has established that selective inhibition of Grp94 via eye drops can offer a safe and effective therapeutic option to treat hereditary forms of glaucoma by utilizing a mechanism of action that differs from currently available agents, potentially without adverse effects. In this Phase 1, Grannus will optimize the efficacy, selectivity over other Hsp90 isoforms, and the physicochemical properties of Grp94 inhibitors using a rational, structure-based approach to construct a new lead compound. Aim 1. Synthesis of rationally designed Grp94 inhibitors using the data gathered from solution of the co-crystal structures and prior structure-activity relationship studies. The working hypothesis is that introduction of conformational constraint and different functional groups into current Grp94-selective inhibitor scaffolds will increase the selectivity (over other Hsp90 isoforms), binding affinity, and drug-like properties of the designed analogs. Aim 2. Evaluate the Grp94 inhibitors prepared in Aim 1 for their effectiveness in in vitro models of myocilin aggregation. Effective compounds will undergo additional analyses for in vivo efficacy, safety and distribution measurement experiments. Upon completion of the proposed work, we will have identified a lead compound with improved pharmacokinetic and pharmacodynamic profile to progress further into IND-enabling studies. The results from Phase II will serve toward completion of an IND-application and subsequently, initiation of clinical studies.

抽象的突变的肌动蛋白（Myoc）的聚集，一种在小梁的内质网（ER）中发现的蛋白网状工厂（TM）细胞，破坏了眼睛水性幽默的流出，导致眼内增加压力（IOP），进行性视网膜神经节细胞（RGC）死亡和视神经的变性，导致原发性开角青光眼（POAG），其特征是视力丧失。大约5％的POAG和35％少年开角青光眼（JOAG）患者表现出青光眼，这是由突变体聚集驱动的 Myoc的形式。我们的研究小组确定了内质网（ER）的HSP90同工型，葡萄糖 - 调节的蛋白94（GRP94），对于突变体肌动蛋白聚集体的组装所必需。实际上，我们的小组证明GRP94抑制剂在体内有效治疗这种遗传性青光眼。有趣的是，GRP94 抑制作用还可以防止由类固醇驱动的IOP；导致二次类固醇引起的条件青光眼（SIG）。这些数据表明，GRP94抑制剂具有治疗任何开角青光眼的潜力。当前的青光眼治疗，例如β受体阻滞剂和前列腺素类似物，仅处理疾病而不是根本原因。我们通过GRP94抑制的方法代表了一个独特的机会处理突变体Myoc驱动的POAG并允许患有SIG的人保持其类固醇方案没有牺牲他们的视力。该应用程序旨在确保优化GRP94抑制剂的资金提高选择性的选择性，适用于眼部给药的物理化学特性以及在动物模型中对优化候选者进行临床前评估。大学的初步工作巴黎圣母院和佛罗里达大学已经确定，通过眼滴对Grp94的选择性抑制提供安全有效的治疗选择，通过利用一种机制来治疗遗传形式的青光眼与当前可用的代理不同的作用可能没有不利影响。在这个阶段1中，Grannus 将优化其他HSP90同工型的疗效，选择性以及GRP94的理化特性使用基于理性的，基于结构的方法来构建新的铅化合物的抑制剂。目标1。合成使用从共晶结构解决方案收集的数据和先验的数据，合理设计的GRP94抑制剂结构活性关系研究。工作假设是构象约束的引入当前GRP94选择性抑制剂支架中的不同官能团将提高选择性（超过设计类似物的其他HSP90同工型），结合亲和力和类似药物样性能。目标2。评估在AIM 1中制备的GRP94抑制剂在肌动蛋白聚集的体外模型中有效。有效的化合物将对体内功效，安全性和分布测量进行其他分析实验。拟议的工作完成后，我们将确定一个铅化合物，并有所改进药代动力学和药效学概况，进一步发展为辅助研究。结果第二阶段将用于完成辅助申请，随后启动临床研究。