Optimizing NGF for Topical Treatment of Glaucoma

优化 NGF 局部治疗青光眼

• 批准号: 10757536
• 负责人: Soon Seog Jeong
• 金额: $ 98.11万
• 依托单位: HUMAN CELL CO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757536
• 关键词: Age; Animal Model; Apoptosis; Astrocytosis; Attenuated; Axon; Axonal Transport; Benefits and Risks; Bilateral; Binding; Blindness; Cauterize; Cell Proliferation; Cell Survival; Cell physiology; Characteristics; Chronic; Clinical Trials; Contrast Sensitivity; Corneal Ulcer; Cyclic GMP; Cytoprotection; Data; Disease; Disease model; Dose; Drug usage; Dry Eye Syndromes; Electrophysiology (science); Engineering; Escherichia coli; Eye; Eyedrops; FDA approved; Glaucoma; Goals; Half-Life; Human; Hypotensives; Individual; Licensing; Life; Mammalian Cell; Mediating; Microspheres; Modeling; Modification; Mus; NGFR Protein; Nerve Growth Factors; Neurotrophic Keratitis; Neurotrophic Tyrosine Kinase Receptor Type 1; Open-Angle Glaucoma; Optic Nerve; Oryctolagus cuniculus; Patients; Persons; Pharmaceutical Preparations; Phase; Phase Ib Clinical Trial; Physiologic Intraocular Pressure; Placebo Control; Population; Pre-Clinical Model; Process; Proteins; Rattus; Receptor Protein-Tyrosine Kinases; Recombinants; Retina; Retinal Ganglion Cells; Risk Factors; Running; Safety; Saimiri; Sclera; Scotoma; Serum; Signal Transduction; Site; Small Business Innovation Research Grant; System; Time; Topical application; Toxic effect; Treatment Factor; Tumor Necrosis Factor Receptor; Veins; Visual Acuity; Work; blind; clinically relevant; conjunctiva; cost; cost effective; design; diabetic; diabetic ulcer; drug development; efficacy validation; experience; eye dryness; improved; innovation; manufacture; modifiable risk; neuroprotection; nonhuman primate; novel therapeutics; pharmacologic; phase 1 study; preservation; prevent; protein expression; research clinical testing; response; retinal ganglion cell degeneration; safety study; side effect; sight restoration; success; translation to humans

ABSTRACT Glaucoma is a leading cause of irreversible vision loss, which is characterized by progressive degeneration of retinal ganglion cells (RGC) and their optic nerve axons. While age is a key risk factor, elevated intraocular pressure (IOP) is the only modifiable risk factor, with topical IOP-lowering drugs as the first line treatment. However, RGC degeneration and vision loss continues in half the patients taking these medications. By the time when characteristic visual field defects are detected, 30-50% of the RGCs have already been lost. Thus, there is an urgent need to develop novel therapies, independent of IOP reduction, which protect RGCs from degeneration and boost the function of RGCs challenged in the disease. The binding of nerve growth factor (NGF) to TrkA attenuates reactive astrocytosis and promotes RGC survival and proliferation. In contrast, the binding to p75NTR leads to astrocytosis and RGC apoptosis. Serum levels of NGF are reduced in early and moderate glaucoma patients compared to healthy controls. Wildtype human NGF (OxervateTM, Cenegermim, Dompe) was approved by FDA in 2018 as eye drops to treat neurotrophic keratitis. In a recent Phase 1b clinical trial, it has been shown that topical use of Cenegermim was safe and tolerable in open-angle glaucoma patients. However, wildtype NGF treatment failed to provide neuroprotection in preclinical models of established glaucoma, antagonized by up-regulated p75NTR activity. Moreover, inefficient manufacturing of Cenegermim using an E coli expression system compromises protein stability and quality at a prohibitive cost for chronic treatment. In the Phase 1 study, we successfully reached all the milestones by designing and validating a human NGF mutein, HC201. The mutein preserves protein stability and expression with enhanced TrkA receptor activities but abrogated p75NTR binding and signaling. In rat models of glaucoma induced by episcleral vein cauterization, topical treatment with HC201 robustly protected RGCs. In contrast, wildtype NGF was not effective. HC201 efficacy was also observed in diabetic corneal ulcer and dry eye disease models. Meanwhile, we have developed a highly cost-effective and scalable process to produce HC201 in mammalian cells. In the Phase II SBIR application, we will continue to validate the efficacy and elucidate mechanism of action in the inducible microbead occlusion model of glaucoma in rats and squirrel monkeys. The use of different approaches to elevate IOP in two species will significantly improve the success for translation to human clinical trials. With a highly experienced drug development team, we also will initiate critical activities necessary to enable IND filing. Specific Aims include: 1) Determine whether topical treatment with HC201 preserves retinal integrity and function compared to the placebo control using the microbead occlusion model of glaucoma in rats and squirrel monkeys; 2) Manufacture cGMP grade HC201 from 100L engineering run; 3) Evaluate nonclinical safety of repeat dose HC201. The long-term goal is to develop HC201, alone or in combination with current hypotensive medication, to preserve and even restore vision in glaucoma patients.

抽象的 青光眼是视力丧失的主要原因，其特征是进行性变性 视网膜神经节细胞（RGC）及其视神经轴突。虽然年龄是关键的危险因素，但人工体内升高 压力（IOP）是唯一可修改的危险因素，局部降低IOP药物作为第一行治疗。 但是，在服用这些药物的一半患者中，RGC退化和视力丧失持续。到......的时候 当检测到特征视野缺陷时，30-50％的RGC已经丢失。因此，那里 迫切需要开发独立于IOP减少的新型疗法，从而保护RGC免受 退化和增强RGC在疾病中挑战的功能。 神经生长因子（NGF）与TRKA的结合减弱了反应性星形细胞增多症并促进RGC 生存和增殖。相比之下，与P75NTR的结合导致星形细胞增多症和RGC凋亡。血清 与健康对照组相比，早期和中度青光眼患者的NGF水平降低。野生型 人类NGF（Oxervatetm，cenegermim，dompe）在2018年被FDA批准，因为眼睛滴剂治疗 神经营养性角膜炎。在最近的1B期临床试验中，已经表明局部使用切晶 在开角青光眼患者中安全可容忍的。但是，野生型NGF治疗未能提供 已建立青光眼的临床前模型中的神经保护作用，由上调的p75NTR活性拮抗。 此外，使用E大肠杆菌表达系统效率低下的葡萄干制造损害了蛋白质 慢性治疗的稳定性和质量以高昂的成本。 在第一阶段研究中，我们通过设计和验证人类NGF成功地达到了所有里程碑 Mutein，HC201。静态蛋白可保留具有增强的TRKA受体活性的蛋白质稳定性和表达 但是废除了p75NTR结合和信号传导。在由粘膜静脉烧焦引起的青光眼大鼠模型中， HC201局部治疗可牢固保护RGC。相反，野生型NGF无效。 HC201 在糖尿病角膜溃疡和干眼病模型中还观察到功效。同时，我们已经发展 在哺乳动物细胞中产生HC201的高度成本效益和可扩展的过程。在II期SBIR中 应用，我们将继续验证可诱导的Microbead中的功效和阐明作用机理 大鼠和松鼠猴子青光眼的闭塞模型。使用不同方法来提升IOP 两个物种将显着改善转化为人类临床试验的成功。拥有经验丰富的 药物开发团队，我们还将发起至关重要的活动以实现IND申请。 具体目的包括：1）确定使用HC201的局部处理是否保留视网膜完整性和 与安慰剂对照相比，使用大鼠和松鼠的青光眼的微粒闭塞模型进行了功能 猴子； 2）从100L工程运行中生产CGMP级HC201； 3）评估非临床安全 重复剂量HC201。 长期目标是单独开发HC201，或与当前的降压药物结合使用，以 在青光眼患者中保存甚至恢复视力。