Preclinical Analysis of Ischemic Optic Nerve Treatment

摘要 非动脉炎性前部缺血性视神经病变（NAION）是一种视神经（ON）卒中。它是最常见的 突然ON相关的视力丧失的原因，发生在世界各地，并影响超过10，000美国人， 年;没有临床有效的治疗方法。之前的所有NAION临床治疗试验都失败了。我们 不仅创造了NAION的啮齿动物模型（rNAION），更重要的是， 灵长类动物模型NAION（pNAION），并开发了分析工具，以精确和准确地测量 潜在的神经保护治疗后的结构和功能改善。我们以前的工作 证明前列腺素J2（PGJ 2）显著降低ON损伤并改善功能 在非人灵长类动物中缺血几小时后给药。这是第一种被证明有这种作用的药物。 然而，NAION患者通常在症状开始后数天出现。因此，我们必须确定一种治疗方法， 这将改善视觉功能，即使在症状出现后几天开始。如果PGJ 2仍然有效 当在该模型中视神经缺血发展后数天给予时， 在人类NAION病例中有效。 我们最近发现炎症在NAION中起着关键作用，并假设靶向治疗是NAION的一种治疗方法。 有效治疗NAION的关键。我们的团队包括一位生物工程师，他彻底改变了 纳米粒子在人类疾病治疗中的应用我们已经发现，树枝状聚合物纳米颗粒可以“回家”， 在rNAION和pNAION两者中ON损伤，并且可以被设计为在延长的时间内释放它们的化合物。 时间周期，使精确，有针对性的，长期的药物输送，潜在地提高药物的有效性。 我们的多学科团队现已将PGJ 2连接到树枝状聚合物纳米颗粒（D-PGJ 2）上，并在 rNAION。我们已经发现D-PGJ 2在ON缺血后保护视网膜神经节细胞（RGC），具有效力 至少相当于游离药物的玻璃体内给药，降低了眼内给药的风险。 我们的建议有两个具体目标。每个目标都使用pNAION模型。我们评估治疗效果 通过体内成像、电生理学、免疫组织化学和定量分析RGC和轴突， 生存 1.确定单次玻璃体内注射PGJ 2的有效性的时间窗。 我们将在pNAION诱导后的不同时间玻璃体内给予可溶性PGJ 2，并确定在诱导后的多长时间内， 在NAION后，PGJ 2具有神经保护作用。 2.确定纳米颗粒连接的PGJ 2（D-PGJ 2）是否保留RGC并改善视觉功能 pNAION后恢复，无全身或眼部毒性。我们将确定D-PGJ 2的细胞特异性 靶向和持续的药物释放可以提供更大的神经保护和功能恢复， pNAION诱导后玻璃体内注射PGJ 2，没有IVT注射的固有潜在风险。

Abstract Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke. It is the most common cause of sudden ON-related vision loss, occurring worldwide, and affecting more than 10,000 Americans every year; there are no clinically effective treatments. Every previous NAION clinical treatment trial has failed. We have created not only a rodent model of NAION (rNAION) but even more importantly, the first nonhuman primate model of NAION (pNAION) and have developed analytical tools to precisely and accurately measure structural and functional improvements after potential neuroprotective treatments. Our previous work demonstrated that Prostaglandin J2 (PGJ2) significantly reduces ON damage and improves function when given several hours after ischemia in nonhuman primates. This is the first drug shown to do so. However, patients with NAION often present days after symptoms begin. Thus, we must identify a treatment that will improve visual function even when begun several days after symptom onset. If PGJ2 is still effective when given several days after the development of optic nerve ischemia in this model, then it is likely to be effective in cases of human NAION. We recently found that inflammation plays a key role in NAION and hypothesize that targeted therapies are a key to effective NAION treatment. Our team includes a bioengineer who has revolutionized the use of nanoparticles in human disease treatment. We have discovered that dendrimer nanoparticles can `home in' on the ON lesion in both rNAION and pNAION and can be designed to release their compound over a prolonged time period, enabling precise, targeted, long-term drug delivery, potentially enhancing a drug's effectiveness. Our multidisciplinary team has now attached PGJ2 to dendrimer nanoparticles (D-PGJ2) and tested it in rNAION. We have found that D-PGJ2 protects retinal ganglion cells (RGCs) after ON ischemia, with a potency at least equivalent to intravitreal administration of the free drug, reducing the risks of intraocular administration. Our proposal has two specific aims. Each aim uses the pNAION model. We evaluate treatment effectiveness by in vivo imaging, electrophysiology, immunohistochemistry, and quantitative analysis of RGC and axon survival. 1. Determine the time window of opportunity for efficacy of a single intravitreal injection of PGJ2. We will administer soluble PGJ2 intravitreally at different times after pNAION induction and identify how long after NAION presents that PGJ2 is neuroprotective. 2. Determine if nanoparticle-linked PGJ2 (D-PGJ2) preserves RGCs and improves visual functional recovery after pNAION without systemic or ocular toxicity. We will determine if D-PGJ2's cell-specific targeting and sustained drug release can provide greater neuroprotection and functional recovery than an intravitreal injection of PGJ2 after pNAION induction, without the inherent potential risks of an IVT injection.