Amadorins as a Novel Oral Therapeutic for Diabetic Retinopathy

Amadorins 作为糖尿病视网膜病变的新型口服疗法

• 批准号: 10601168
• 负责人: RAJA G KHALIFAH
• 金额: $ 29.89万
• 依托单位: PRAETEGO, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601168
• 关键词: Acceleration; Address; Adult; Advanced Glycosylation End Products; Affect; Age; Age Years; American; Antibodies; Antioxidants; Behavior assessment; Behavioral; Bilateral; Binding; Blindness; Blood Vessels; Brain; Cell Death; Cell Survival; Clinical Management; Clinical Trials; Complications of Diabetes Mellitus; Confocal Microscopy; Contrast Sensitivity; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Disease; Drug Kinetics; Effectiveness; Endophthalmitis; Endowment; Excretory function; Eye diseases; Female; Free Radicals; Frequencies; Funding; Glucose; Goals; Grant; Healthcare; Hour; Hyperglycemia; Immunohistochemistry; Incidence; Inflammation; Injections; Investigation; Investigational Drugs; Investigational New Drug Application; Ions; Lesion; Link; Long-Evans Rats; Measures; Metabolism; Metals; Microvascular Dysfunction; Modeling; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Nerve Degeneration; Neurons; Neuroprotective Agents; Optical Coherence Tomography; Oral; Oral Administration; Organ; Outcome; Oxidation-Reduction; Oxidative Stress Induction; Pain; Patients; Penetration; Peripheral Nervous System Diseases; Permeability; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Pre-Clinical Model; Process; Production; Property; Proteins; Pyridoxamine; Pyruvaldehyde; Rattus; Reaction; Reactive Oxygen Species; Retina; Retinal Diseases; Retinal Ganglion Cells; Risk; Running; Safety; Small Business Technology Transfer Research; Sodium Chloride; Sprague-Dawley Rats; Streptozocin; Streptozocin Diabetes; Testing; Therapeutic; Thick; Tissues; Vision; absorption; adduct; amino group; bevacizumab; chemical property; cohort; diabetic; diabetic rat; drug candidate; effectiveness evaluation; inhibitor; lead candidate; male; meetings; mild cognitive impairment; neuroprotection; neurovascular injury; non-diabetic; novel; novel strategies; oxidation; preclinical efficacy; preclinical study; prevent; retinal damage; small molecule; small molecule therapeutics

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.

项目摘要 糖尿病视网膜病变（DR）是一种严重的糖尿病并发症，是导致视力下降的主要原因， 成年人，在美国影响超过750万人。它造成的新失明病例比任何 18至65岁人群的其他眼病。抗VEGF治疗可以减缓进展 但仅在已经发生显著血管病变后使用。这些 眼内抗体注射对患者来说是昂贵的、痛苦的、不方便的，并且引入了发展成 眼内炎成功开发出一种口服小分子治疗药物，可保护 在疾病的早期阶段的视网膜将代表临床管理的重大突破 糖尿病并发症的症状Praetego Inc.计划通过开发一种新的口服药物来解决DR问题， 在疾病的早期阶段保护视网膜免受高血糖的损害。hyperplasia是 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， 所谓的晚期糖基化终产物（AGEs），这一过程伴随并加速了糖基化终产物的产生。 破坏二羰基化合物如丙酮醛、活性氧和自由基。有许多证据 表明AGE形成是糖尿病所有微血管并发症的致病因素。我们的项目 我们开发了新型强效AGE抑制剂PTG-630，用于治疗DR，显示出神经保护作用 糖尿病周围神经病变（DPN）的临床前研究。它强烈结合氧化还原金属离子，特别是Cu 2+， 这赋予它作为一般抗氧化剂的额外能力。PTG-630已被充分表征 在安全药理学和ADME（吸收、分布、代谢、排泄）和理化方面 特性.这种双重作用的小分子具有良好的渗透到大脑和脑脊液口服后， 由于其优异的细胞渗透性，可用于给药。在初步的药代动力学研究中， 证实它很快到达视网膜，一个有证据表明神经血管损伤的器官 因此，在第一阶段的建议中，我们将测试以下假设： 给予PTG-630可以预防STZ-1中的视网膜神经变性、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（以其三盐酸盐形式）预防 在链脲佐菌素（STZ）-糖尿病模型中，使用雌性长- Evans大鼠;和2）在雄性Long-Evans大鼠中做同样的事情。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 使用谱域光学相干断层扫描（SD-OCT）的内部和外部视网膜厚度;以及c） 测量AGE积累、大神经胶质反应性和视网膜神经节细胞存活。成功完成 该项目将提供数据支持计划的第二阶段STTR提交的更全面的研究， 在早期的IND前FDA会议后帮助准备IND使能研究。