Amadorins as a Novel Oral Therapeutic for Diabetic Retinopathy

项目总结 糖尿病视网膜病变(DR)是一种严重的糖尿病并发症，是导致工作中视力丧失的主要原因。 老年人，影响到美国超过750万人。它导致的新失明病例比以往任何时候都多 18岁至65岁人群中的其他眼病。抗血管内皮生长因子治疗可以延缓病情进展。 在许多患者中使用，但只有在发生重大血管病变后才使用。这些 眼内抗体注射昂贵、痛苦，对患者不方便，并会带来发展的风险。 眼内炎。一种口服小分子药物的成功研制 疾病早期的视网膜将代表着临床治疗的重大突破。 糖尿病并发症的风险。Praetego Inc.计划通过开发一种新的口服药物来解决DR问题，该药物可能 在疾病的早期阶段保护视网膜免受高血糖的损害。高血糖是 连接所有糖尿病并发症的关键共同因素。蛋白质与葡萄糖直接反应形成 所谓的晚期糖基化终末产物(AGEs)，这一过程伴随和加速了 破坏甲基乙二醛、活性氧基和自由基等二羰基。有很多证据表明 提示年龄的形成是糖尿病所有微血管并发症的致病因素。我们的项目 推出我们的新型有效的AGE抑制剂PTG-630，用于治疗具有神经保护作用的DR 关于糖尿病周围神经病变(DPN)的临床前研究。它热衷于结合氧化还原金属离子，特别是Cu2+， 这赋予了它作为一种普通抗氧化剂的额外能力。PTG-630已经得到了很好的表征 安全药理学和ADME(吸收、分布、代谢、排泄)和物理化学 属性。这种双重作用的小分子口服后可以很好地渗透到大脑和脑脊液中。 由于其良好的细胞渗透性，给药。在初步的药代动力学研究中，我们有 证实它很快就到达视网膜，视网膜是一个有神经血管损伤证据的器官 因此，在这个第一阶段的提案中，我们将检验这样的假设：口头 应用PTG-630可预防STZ视网膜神经变性、视力丧失和视网膜炎症 糖尿病大鼠。我们的具体目标是：1)确定PTG-630(其三氯化盐形式)预防 链脲佐菌素(STZ)-糖尿病模型中的视力损失和糖尿病视网膜病变 2)在雄性Long-Evans大鼠身上做同样的事情。我们将通过a)测量视觉功能来实现这一点 通过行为视动分析，使用空间频率阈值和对比敏感度；b)测量 使用光谱域光学相干断层扫描(SD-OCT)的视网膜内外厚度；以及c) 测量年龄积累、大胶质细胞反应性和视网膜神经节细胞存活率。成功完成 该项目将通过计划中的第二阶段STTR提交提供数据，以支持更彻底的研究，同时 在早期的IND前FDA会议后，帮助准备启用IND的研究。

PROJECT SUMMARY Diabetic Retinopathy (DR) is a serious diabetic complication that is the leading cause of vision loss in working- age adults, affecting more than 7.5 million people in the USA. It causes more new cases of blindness than any other eye disease in people between the ages of 18 and 65. The anti-VEGF treatments can slow the progress of DR in many patients but are only used after significant vascular lesions have already developed. These intraocular antibody injections are expensive, painful, inconvenient for patients and introduce a risk of developing endophthalmitis. The successful development of an orally administered small molecule therapeutic that protects the retina at an earlier stage of the disease would represent a significant breakthrough in the clinical management of this diabetic complication. Praetego Inc. plans to address DR by developing a novel oral medication that may protect the retina from the damage of hyperglycemia at the earliest stages of the disease. Hyperglycemia is the key common factor linking all diabetic complications. Direct reaction of proteins with glucose leads to formation of so-called advanced glycation end products (AGEs), a process accompanied and accelerated by production of damaging dicarbonyls such as methylglyoxal, reactive oxygen species and free radicals. There is much evidence implicating AGE formation as a causative factor in all microvascular complications of diabetes. Our project advances our novel and potent AGE inhibitor, PTG-630, for treating DR, which is demonstrating neuroprotection in preclinical studies on diabetic peripheral neuropathy (DPN). It avidly binds redox metal ions, especially Cu2+, which endows it with the additional capacity to be a general antioxidant. PTG-630 has been well characterized in safety pharmacology and ADME (absorption, distribution, metabolism, excretion), and physical-chemical properties. This dual-acting small molecule has excellent penetration into the brain and CSF after oral administration due to its excellent cellular permeability. In preliminary pharmacokinetic studies, we have confirmed that it quickly reaches the retina, an organ where there is evidence of neurovascular damage preceding vascular lesions in DR. Thus, in this Phase I proposal, we will test the hypothesis that: orally administered PTG-630 can prevent retinal neurodegeneration, vision loss and retinal inflammation in STZ- diabetic rats. Our Specific Aims are: 1) determine the effectiveness of PTG-630 (in its tri-HCl salt form) to prevent vision loss and diabetes-induced retinal disease in the streptozotocin (STZ)-diabetes model using female Long- Evans rats; and 2) do the same in male Long-Evans rats. We will accomplish this by a) measuring visual function through behavioral optokinetic analysis, using spatial frequency threshold and contrast sensitivity; b) measuring inner and outer retinal thickness using spectral domain optical coherence tomography (SD-OCT); and c) measuring AGE accumulation, macro-glial reactivity, and retinal ganglion cell survival. Successful completion of this project will provide data supporting more thorough studies by a planned Phase II STTR submission while helping prepare for IND-enabling studies following an early pre-IND FDA meeting.