A TrkB Activator for Treatment of Glaucoma

用于治疗青光眼的 TrkB 激活剂

• 批准号: 10039602
• 负责人: JEFFREY H BOATRIGHT
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039602
• 关键词: Age; Aging; Anterior; Aqueous Humor; Blast Injuries; Blindness; Blood-Retinal Barrier; Brain; Brain-Derived Neurotrophic Factor; Cell physiology; Cells; Cessation of life; Chronic; Chronic Disease; Clinic; Clinical Trials; Data; Disease; Disease Progression; Dose; Etiology; Eye; General Population; Glaucoma; Half-Life; Health; Hour; Human; Intraperitoneal Injections; Mediator of activation protein; Microspheres; Modeling; Monitor; Morphology; Mus; Neurotrophic Tyrosine Kinase Receptor Type 2; Ocular Hypertension; Optic Nerve; Outcome; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiologic Intraocular Pressure; Population; Prevalence; Recombinants; Refractory; Reporting; Retina; Retinal Ganglion Cells; Risk Factors; Survivors; Testing; Time; Topical application; Toxicology; Translating; Veterans; Vision; Visual; Visual impairment; Woman; Work; aged; analog; cell killing; compliance behavior; design; effective therapy; epidemiology study; experimental study; high risk; human disease; in vivo; insight; men; mouse model; neurotrophic factor; novel strategies; pigment dispersion syndrome; pre-clinical; response; retinal axon; retinal damage; small molecule; standard of care; success; treatment strategy

Glaucoma is a serious and growing health problem for our nation's Veterans. At least 285,000 Veterans (possibly over 700,000) have this chronic disease, the leading cause of irreversible blindness globally. Prevalence is greater among Veterans than in the general population and is increasing dramatically. Women Veterans and blast injury survivors are at higher risk for developing glaucoma as they age. Glaucoma is a serious problem for our nation's Veterans; we intend to do something about this. The greatest risk factors associated with glaucoma are elevated intraocular pressure (IOP) and age. Elevated IOP damages retinal ganglion cells (RGCs), causing blindness. Initially many patients respond well to topically-applied IOP-lowering drugs, but disease often returns over time. Given the aging Veteran population, there is thus an urgent need to develop new treatment strategies for late-stage disease. We propose a new, IOP-independent approach that directly protects RGCs by treating with a synthetic analog to Brain-Derived Neurotrophic Factor (BDNF) that we developed to protect RGCs from ocular blast injury, N-[2-(5-hydroxy-1H- indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC). We hypothesize that treatment with HIOC will slow or stop vision loss and protect RGCs in mouse models of glaucoma, including in aged mice. We propose two aims to test this hypothesis: Aim 1: To assess the feasibility of using a TrkB activator as a treatment for glaucoma, we will test whether HIOC treatment protects RGCs and vision in a mouse model of induced ocular hypertension. Hypothesis: TrkB activation by HIOC treatment will protect against RGC loss in a mouse model of induced, elevated IOP. IOP elevation will be induced by injecting microbeads into the ocular anterior segment to impede aqueous humor outflow. The resulting loss of RGCs and visual function mimics disease etiology observed in human glaucoma patients. HIOC will be given systemically by intraperitoneal injection at various times relative to induction and at various doses. Visual function, morphological, and toxicological outcomes will be assessed over time. To confirm that chronic, repeated HIOC treatment activates TrkB over time, the phosphorylation of TrkB and downstream mediators will be examined. Also, HIOC will be co-administered with a TrkB receptor antagonist to confirm protection specifically in a glaucoma model occurs through TrkB activation. Aim 2. To gain additional translational insight, test whether HIOC treatment is protective in a naturally- occurring glaucoma mouse model, the DBA/2J mouse. Hypothesis: TrkB activation induced by HIOC treatment will be protective in a naturally-occurring glaucoma model whose etiology includes late-onset, gradual elevation of IOP, RGC loss, and vision loss, as seen in human disease. The DBA/2J mouse develops pigment dispersion syndrome. Like many human glaucomas, the DBA/2J model is sporadic and progressive. This makes it a cumbersome model for testing multiple experimental permutations (as proposed in Aim 1), but a logical and powerful test for HIOC efficacy. To increase translational relevance, treatment will start after IOP elevation but prior RGC loss. These studies will test whether a BDNF TrkB receptor activator protects RGCs and vision in complementary mouse models of glaucoma. Similar to how we developed and brought another drug to trial (NCT02841306), this project contains proof-of-principle, mechanistic, and translationally-oriented experiments that will add to preclinical data in support of our proposing ophthalmic clinical trials of HIOC, a potentially inexpensive treatment for Veterans suffering from a currently intractable, chronic disease that results in blindness.

青光眼对于我们国家的退伍军人来说是一个严重且日益严重的健康问题。至少285,000名退伍军人 （可能超过700,000）患有这种慢性病，这是全球不可逆失明的主要原因。 退伍军人的患病率比普通人群更大，并且正在急剧增加。女性 退伍军人和爆炸损伤幸存者随着年龄的增长而患青光眼的风险更高。青光眼是 对我们国家的退伍军人的严重问题；我们打算为此做些事情。 与青光眼相关的最大危险因素是眼内压（IOP）和年龄升高。 IOP升高的视网膜神经节细胞（RGC）升高，导致失明。最初许多患者对 局部使用的降低IOP药物，但疾病通常会随着时间的流逝而恢复。鉴于老化的退伍军人， 因此，迫切需要为晚期疾病制定新的治疗策略。我们提出了一个新的 IOP独立的方法，通过用脑衍生的合成类似物处理直接保护RGC 我们开发的神经营养因子（BDNF）是为了保护RGC免受眼部爆炸损伤，N- [2-（5-Hydroxy-1H-） 吲哚-3-基）乙基] -2-氧化吡啶-3-羧酰胺（HIOC）。我们假设使用HIOC治疗会放慢 或停止视力丧失并保护青光眼小鼠模型（包括老年小鼠）中的RGC。我们 提出了两个目的，以检验这一假设： 目标1：评估使用TRKB激活剂作为青光眼治疗的可行性，我们将测试 HIOC治疗是否可以保护RGC和视力在诱导眼高血压的小鼠模型中。 假设：通过HIOC治疗激活TRKB将在诱导的小鼠模型中预防RGC损失， 升高的IOP。 IOP高程将通过将微粒注入眼前部分来诱导 水幽默流出。在 人青光眼患者。 HIOC将通过腹膜内注射在不同时间的相对时系统地给出 诱导和各种剂量。将评估视觉功能，形态学和毒理学结果 随着时间的推移。为了确认慢性，重复的HIOC处理会随着时间的推移激活TRKB 将检查TRKB和下游介体。此外，HIOC将与TRKB受体共同管理 通过TRKB激活发生拮抗剂在青光眼模型中专门确认保护。 目标2。要获得额外的翻译见解，请测试HIOC治疗是否自然保护 - 发生的青光眼小鼠模型，DBA/2J小鼠。假设：HIOC诱导的TRKB激活 治疗将在天然呈现的青光眼模型中具有保护作用，该模型的病因包括晚发， IOP，RGC丢失和视力丧失的逐渐升高，如人类疾病所见。 DBA/2J鼠标发展 色素分散综合征。像许多人类青光眼一样，DBA/2J模型是零星和进步的。 这使其成为测试多个实验排列的繁琐模型（如AIM 1中提出），但 HIOC功效的逻辑和强大测试。为了提高转化相关性，治疗将在IOP之后开始 高程但先前的RGC损失。 这些研究将测试BDNF TRKB受体激活剂是否保护RGC和互补的视力 青光眼的小鼠模型。类似于我们开发并将另一种药物带入试验的方式（NCT02841306）， 该项目包含原则证明，机理和面向翻译的实验，将添加到 临床前数据支持我们提出的HIOC眼科临床试验，这是一种潜在廉价的 患有目前棘手的慢性疾病的退伍军人的治疗，导致失明。