A TrkB Activator for Treatment of Glaucoma

青光眼是我国退伍军人面临的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70万人)患有这种慢性病，这是全球不可逆转失明的主要原因。 退伍军人的患病率高于普通人群，而且还在急剧增加。女人 退伍军人和冲击伤幸存者随着年龄的增长患青光眼的风险更高。青光眼是一种 对我们国家的退伍军人来说是个严重的问题；我们打算为此做点什么。 与青光眼相关的最大危险因素是高眼压和年龄。 高眼压损害视网膜神经节细胞(RGC)，导致失明。最初，许多患者对 局部应用降眼压药物，但随着时间的推移，疾病往往会复发。考虑到退伍军人人口的老龄化， 因此，迫切需要为晚期疾病开发新的治疗策略。我们提出了一个新的， 不依赖眼压的方法，通过使用合成的脑源性类似物直接保护视网膜节细胞 我们开发的用于保护视网膜节细胞免受眼冲击伤的神经营养因子，N-[2-(5-羟基-1H- Indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide(HIOC)。我们假设HIOC的治疗将会减慢 或者阻止青光眼小鼠模型的视力丧失和保护视网膜节细胞，包括老年小鼠。我们 提出两个目标来检验这一假设： 目的1：为了评估使用TrkB激活剂治疗青光眼的可行性，我们将测试 HIOC治疗对诱导性高眼压小鼠视网膜神经节细胞和视力是否有保护作用。 假设：通过HIOC处理激活TrkB将保护RGC丢失，在诱导的， 眼压升高。眼球前段注射微珠可引起眼压升高 房水流出。由此导致的视网膜节细胞和视觉功能的丧失与在 人类青光眼患者。HIOC将在不同的时间通过相对的腹腔注射进行系统的给药 以不同的剂量进行诱导。将评估视觉功能、形态和毒理学结果 随着时间的推移。为了证实长期、重复的HIOC治疗随着时间的推移激活TrkB， 将审查TrkB和下游调解人。此外，HIOC将与TrkB受体联合给药 在青光眼模型中，拮抗剂通过激活TrkB来确认保护作用。 目的2.为了获得更多的翻译洞察力，测试HIOC治疗在自然- 建立小鼠青光眼模型，建立DBA/2J小鼠模型。假设：HIOC诱导TrkB激活 在自然发生的青光眼模型中，治疗将具有保护性，其病因包括晚发性青光眼， 眼压逐渐升高、RGC丧失和视力丧失，如人类疾病所见。DBA/2J小鼠研制成功 色素弥散综合征。像许多人类青光眼一样，DBA/2J模型是零星的和渐进性的。 这使得它成为测试多个实验排列的繁琐模型(如目标1中所建议的)，但是 这是对HIOC疗效的一次合理而有力的测试。为了增加翻译相关性，治疗将在眼压后开始 提升，但之前的RGC损失。 这些研究将测试BDNF TrkB受体激活剂是否保护视网膜神经节细胞和视觉互补 青光眼的小鼠模型。类似于我们开发和试验另一种药物的方式(NCT02841306)， 该项目包含原则证明、机械性和面向翻译的实验，这些实验将增加 临床前数据支持我们提出的HIOC眼科临床试验，这是一种潜在的廉价药物 治疗患有一种目前难以治愈的导致失明的慢性疾病的退伍军人。

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.