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.

摘要 青光眼是一种以进行性变性为特征的不可逆视力丧失的主要原因 视网膜神经节细胞（RGC）及其视神经轴突的。虽然年龄是一个关键的风险因素， 眼压（IOP）是唯一可改变的风险因素，局部降IOP药物作为一线治疗。 然而，在服用这些药物的一半患者中，RGC变性和视力丧失仍在继续。的时候 当检测到特征性视野缺陷时，30-50%的RGC已经丢失。因此 迫切需要开发新的治疗方法，独立于IOP降低，保护RGC免受 在疾病中受到挑战的RGC的变性和增强功能。 神经生长因子（NGF）与TrkA的结合减弱反应性星形胶质细胞增生并促进RGC 生存和增殖。相反，与p75 NTR的结合导致星形细胞增多和RGC凋亡。血清 与健康对照相比，早期和中度青光眼患者的NGF水平降低。野生型 人神经生长因子（OxervateTM，Cenegermim，Dompe）于2018年被FDA批准作为眼药水用于治疗 神经营养性角膜炎在最近的1b期临床试验中，已显示局部使用Cenegermim 在开角型青光眼患者中安全且可耐受。然而，野生型NGF治疗未能提供 在已建立的青光眼临床前模型中的神经保护作用，通过上调的p75 NTR活性拮抗。 此外，使用大肠杆菌表达系统生产Cenegermim的效率低下， 稳定性和质量而长期治疗成本过高。 在第一阶段的研究中，我们成功地通过设计和验证人类神经生长因子达到了所有的里程碑。 突变蛋白，HC 201。该突变蛋白保留了蛋白质稳定性和表达，同时增强了TrkA受体活性 但废除了p75 NTR结合和信号传导。在巩膜外静脉烧灼诱导的大鼠青光眼模型中， 用HC 201的局部治疗有力地保护了RGC。相反，野生型NGF是无效的。公司简介 在糖尿病性角膜溃疡和干眼病模型中也观察到功效。与此同时，我们开发了 在哺乳动物细胞中生产HC 201的高成本效益和可扩展的方法。在第二阶段SBIR中 应用中，我们将继续验证诱导微珠的功效并阐明其作用机制 大鼠和松鼠猴的青光眼阻塞模型。使用不同的方法来升高IOP， 这两个物种将显著提高人类临床试验的成功率。一个经验丰富的 药物开发团队，我们还将启动必要的关键活动，使IND申请。 具体目的包括：1）确定用HC 201局部治疗是否保留视网膜完整性， 在大鼠和松鼠中使用青光眼的微珠阻塞模型与安慰剂对照相比的功能 猴; 2）从100 L工程运行中生产cGMP级HC 201; 3）评价 重复给药HC 201。 长期目标是开发HC 201，单独使用或与当前的治疗药物联合使用， 保护甚至恢复青光眼患者的视力。