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 糖尿病性视网膜病（DR）是严重的糖尿病并发症，是造成工作中视力丧失的主要原因 年龄成年人，影响美国超过750万人。它会导致比任何人都多的新案件 年龄在18至65岁之间的其他眼病。抗VEGF治疗可以减缓进度 许多患者的DR中的DR，但仅在显着的血管病变后才使用。这些 眼内抗体注射昂贵，痛苦，不便，并引入了发展的风险 内脑膜。成功地开发了一种口服的小分子治疗性，以保护 疾病早期的视网膜将代表临床管理的重大突破 这种糖尿病并发症。 Praetego Inc.计划通过开发一种可能的口服药物来解决DR 在最早的疾病阶段保护视网膜免受高血糖的损害。高血糖是 关键的共同因素连接所有糖尿病并发症。蛋白质与葡萄糖的直接反应导致形成 所谓的高级糖基化末端产品（年龄），该过程伴随并加速了生产 破坏性二烷基，例如甲基甘氨酸，活性氧和自由基。有很多证据 将年龄形成作为糖尿病所有微血管并发症的病因。我们的项目 进步我们的新颖和有效的年龄抑制剂PTG-630，用于治疗DR，这证明了神经保护作用 在临床前研究的糖尿病周围神经病（DPN）中。它非常结合氧化还原金属离子，尤其是Cu2+， 这赋予其额外的能力成为一般抗氧化剂。 PTG-630的特征很好 在安全药理学和ADME中（吸收，分布，代谢，排泄）和物理化学 特性。这种双作用小分子在口服后具有出色的渗透到大脑和CSF 由于其出色的细胞渗透性，给药。在初步的药代动力学研究中，我们有 确认它很快到达了视网膜，这是有神经血管损伤证据的器官 Dr。先前的血管病变。因此，在这个阶段的建议中，我们将检验以下假设：口头 施用的PTG-630可以防止STZ- 糖尿病大鼠。我们的具体目的是：1）确定PTG-630（以Tri-HCl盐形式）的有效性 视力丧失和糖尿病诱导的视网膜疾病（STZ） - 糖尿病模型使用女性长期 埃文斯老鼠； 2）在雄性长鹰队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目标 通过行为光动力学分析，使用空间频率阈值和对比度灵敏度； b）测量 使用光谱域光学相干断层扫描（SD-OCT）的内部和外视网膜厚度；和c） 测量年龄的积累，宏观反应性和视网膜神经节细胞存活。成功完成 该项目将通过计划的II阶段STTR提交提供数据支持更彻底的研究，而 在早期的FDA会议上，帮助准备成熟的研究。