A TrkB Activator for Treatment of Glaucoma

青光眼是一个严重的和日益增长的健康问题，为我们国家的退伍军人。至少285，000名退伍军人 （可能超过70万）患有这种慢性疾病，这是全球不可逆转失明的主要原因。 退伍军人中的患病率高于一般人群，并且正在急剧增加。妇女 退伍军人和爆炸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 这对我们国家的退伍军人来说是一个严重的问题;我们打算做点什么。 与青光眼相关的最大风险因素是眼内压（IOP）升高和年龄。 升高的IOP损害视网膜神经节细胞（RGC），导致失明。最初，许多患者对 局部应用的降眼压药物，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。我们提出一个新的， 通过用脑源性的合成类似物治疗直接保护RGC的IOP非依赖性方法 神经营养因子（BDNF），我们开发，以保护视网膜节细胞免受眼冲击伤，N-[2-（5-羟基-1H- 吲哚-3-基）乙基]-2-氧代哌啶-3-甲酰胺（HIOC）。我们假设HIOC治疗会减缓 或在青光眼小鼠模型中，包括在老年小鼠中，阻止视力丧失并保护RGC。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激活剂作为青光眼治疗的可行性，我们将测试 HIOC治疗是否保护诱导性高眼压小鼠模型中的RGC和视力。 假设：通过HIOC处理的TrkB活化将在诱导的， 眼内压升高。将通过将微珠注射到眼前节中以阻止眼内压升高， 房水流出由此导致的RGC和视觉功能的丧失与在2010年12月至2011年12月期间观察到的疾病病因学相似。 人类青光眼患者。HIOC将通过腹膜内注射在不同时间全身给予， 诱导和不同剂量。将评估视觉功能、形态学和毒理学结局 随着时间为了证实长期重复HIOC处理随时间激活TrkB， 将检查TrkB和下游介质。此外，HIOC将与TrkB受体共同施用。 在青光眼模型中，使用TrkB拮抗剂来确认特异性保护作用是通过TrkB激活发生的。 目标2.为了获得更多的翻译见解，测试HIOC治疗是否在自然条件下具有保护作用， 发生青光眼的小鼠模型，DBA/2 J小鼠。假设：HIOC诱导的TrkB活化 治疗在其病因包括迟发性青光眼的自然发生的青光眼模型中是保护性的， 如在人类疾病中所见，IOP逐渐升高、RGC丧失和视力丧失。DBA/2 J小鼠 色素分散综合征像许多人类肿瘤一样，DBA/2 J模型是散发性和进行性的。 这使得它成为测试多个实验排列的繁琐模型（如目标1中所提出的），但 这是对HIOC有效性的合理而有力的测试。为了增加翻译相关性，治疗将在IOP后开始 升高但先前RGC丧失。 这些研究将测试BDNF TrkB受体激活剂是否在互补性刺激中保护RGCs和视力。 小鼠青光眼模型。类似于我们如何开发并将另一种药物用于试验（NCT 02841306）， 该项目包含了原理验证、机械性和预防性实验，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，一种潜在的廉价 治疗退伍军人患有目前难以治愈的慢性疾病，导致失明。

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.