Optimizing NGF for Topical Treatment of Glaucoma

优化 NGF 局部治疗青光眼

基本信息

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
项目类别：
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

项目摘要

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.

抽象的青光眼是不可逆视力丧失的主要原因，其特征是进行性退化视网膜神经节细胞（RGC）及其视神经轴突。虽然年龄是一个关键的危险因素，但眼压升高压力（IOP）是唯一可改变的危险因素，局部降眼压药物作为一线治疗。然而，服用这些药物的患者中有一半会继续出现视网膜神经节变性和视力丧失。到......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，有迫切需要开发独立于眼压降低的新疗法，以保护 RGC 免受退化并增强受疾病挑战的 RGC 的功能。神经生长因子 (NGF) 与 TrkA 的结合可减弱反应性星形细胞增多并促进 RGC 生存和增殖。相反，与 p75NTR 的结合会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 NGF（OxervateTM、Cenegermim、Dompe）于 2018 年获得 FDA 批准作为滴眼剂治疗神经营养性角膜炎。在最近的 1b 期临床试验中，表明局部使用 Cenegermim 对于开角型青光眼患者安全且可耐受。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发挥神经保护作用，通过上调的 p75NTR 活性来拮抗。此外，使用大肠杆菌表达系统生产 Cenegermim 的效率低下，会损害蛋白质稳定性和质量，但慢性治疗的成本却令人望而却步。在第一阶段研究中，我们通过设计和验证人类 NGF 成功实现了所有里程碑突变蛋白，HC201。突变蛋白通过增强 TrkA 受体活性来保持蛋白质稳定性和表达但废除了 p75NTR 结合和信号传导。在巩膜外静脉烧灼诱导的青光眼大鼠模型中，使用 HC201 进行局部治疗，可有效保护 RGC。相比之下，野生型NGF则无效。 HC201 在糖尿病角膜溃疡和干眼病模型中也观察到了疗效。同时，我们开发了一种在哺乳动物细胞中生产 HC201 的极具成本效益且可扩展的工艺。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青光眼闭塞模型。使用不同的方法来提高眼压两个物种将显着提高转化为人体临床试验的成功率。拥有经验丰富的药物开发团队，我们还将启动 IND 申报所需的关键活动。具体目标包括： 1) 确定 HC201 局部治疗是否能保持视网膜完整性和使用大鼠和松鼠青光眼微珠闭塞模型与安慰剂对照进行功能比较猴子； 2) 从100L工程运行生产cGMP级HC201； 3) 评估非临床安全性重复剂量 HC201。长期目标是开发 HC201，单独或与现有的降血压药物联合使用，以保护甚至恢复青光眼患者的视力。