Oral therapy for diabetic retinopathy using ACE2/Ang1-7 bioencapsulated in plant cells

使用生物封装在植物细胞中的 ACE2/Ang1-7 口服治疗糖尿病视网膜病变

• 批准号: 9128010
• 负责人: HENRY DANIELL
• 金额: $ 40.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128010
• 关键词: Acids; Alzheimer' s Disease; Amyloid; Angiotensin II; Animal Model; Attenuated; Bioreactors; Blood; Blood Circulation; Blood Vessels; Brain; Cardiovascular system; Cell Wall; Cells; Chloroplasts; Chorea; Clinical Trials; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Edible Plants; Encapsulated; Enzymes; Equilibrium; Foundations; Functional disorder; Gene Delivery; Gene Expression; Generations; Genes; Genome; Glucose; Goals; Health; Human; Hyperactive behavior; Inflammation; Inflammatory; Insulin Resistance; Kidney Diseases; Lettuce - dietary; Lipids; Maintenance; Mediating; Microbe; Mus; Myelin Basic Proteins; Neuraxis; Oral; Organ; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Physiology; Plant Leaves; Plants; Prevention; Production; Proteins; Renin-Angiotensin System; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Stomach; Testing; Therapeutic; Tissues; Toxin; Transgenic Organisms; Treatment Efficacy; Vascular Diseases; base; cell type; clinical application; clinical investigation; commensal microbes; cost; diabetic; diabetic patient; endothelial dysfunction; equilibration disorder; glucose metabolism; improved; in vivo; innovation; lipid metabolism; member; neurovascular; novel; novel strategies; oxidative damage; prevent; receptor; receptor mediated endocytosis; relating to nervous system; therapeutic protein; translational study; uptake; vascular inflammation

 DESCRIPTION: Diabetic retinopathy (DR) is the most common diabetic complication developing in both type1 and type2 diabetic patients and insofar is incurable. Hyperactivity of the renin angiotensin system (RAS), resulting in elevated concentrations of Angiotensin II (Ang II), is central to pathways leading to increased vascular inflammation, oxidative stress and endothelial dysfunction in diabetes and its associated complications including DR. The discovery of ACE2 established the existence of a protective axis of the RAS as a key regulator counteracting the deleterious effects of Ang II. We have recently demonstrated that increased expression of ACE2 and Ang1-7, the two key members of the protective axis, via AAV-mediated retinal gene delivery reduced diabetes-induced retinal pathology, validating that enhancing the ACE2/Ang1-7/MAS axis is a promising approach for treating patients with DR. In addition, enhancing Ang1-7 and ACE2 also improves lipid and glucose metabolism, ameliorates insulin resistance and confers protection against a variety of pathological conditions including diabetes-induced nephropathy and cardiovascular dysfunction. Thus an ideal strategy would be to enhance ACE2/Ang1-7 both systemically and locally at target tissues. This proposal takes advantage of an innovative concept based on the use of plant chloroplasts as highly efficient bioreactors for production and oral delivery of therapeutic proteins bio encapsulated in plant cells. The therapeutic protein is fused to chorea toxin subunit B, which not only facilitate the transmucosal transport into circulation, but also enhance tissue cell uptake by GM1 receptor mediated endocytosis. We have recently shown that orally delivered therapeutic proteins are widely distributed in organs including brain and retina crossing blood brain/retina barriers; oral delivery of bio encapsulated myelin basic protein ameliorated amyloid burden in advanced human and mouse Alzheimer's disease brains and retinas, prevented loss of retinal ganglion cells. Thus this novel concept provides a more efficient, low cost production and patient-friendly delivery of therapeutic proteins, particularly to the central nervous system, which has long been a major challenge. The goals of this proposal are to evaluate the efficacy of oral delivery of Ang1- 7 and ACE2 bio encapsulated in plant cells in prevention and treatment of DR in suitable animal models and to generate and characterize transplastomic ACE2 and Ang1-7 expression in edible lettuce in order to advance bio encapsulated protein delivery approach towards clinical investigations. Result from these proposed studies will provide proof-of-concept on feasibility and efficacy in animal models of DR using oral delivery of plant chloroplast- based therapeutic proteins, and set the foundation for initiating clinical trials by oral delivery of bio encapsulate ACE2 and Ang1-7 for prevention and treatment of DR.

 产品说明：糖尿病视网膜病变（DR）是1型和2型糖尿病患者中最常见的糖尿病并发症，目前无法治愈。导致血管紧张素II（Ang II）浓度升高的肾素血管紧张素系统（RAS）的过度活性是导致糖尿病及其相关并发症（包括DR）中血管炎症增加、氧化应激和内皮功能障碍的途径的核心。ACE 2的发现确立了RAS的保护轴作为抵消Ang II有害作用的关键调节剂的存在。我们最近已经证明，通过AAV介导的视网膜基因递送增加保护轴的两个关键成员ACE 2和Ang 1 -7的表达减少了糖尿病诱导的视网膜病理学，验证了增强ACE 2/Ang 1 -7/MAS轴是治疗DR患者的有希望的方法。此外，增强Ang 1 -7和ACE 2还改善脂质和葡萄糖代谢，改善胰岛素抵抗并提供针对多种病理状况的保护，包括糖尿病诱导的肾病和心血管功能障碍。因此，理想的策略将是在靶组织全身和局部增强ACE 2/Ang 1 -7。该提案利用了基于使用植物叶绿体作为高效生物反应器的创新概念，用于生产和口服递送生物封装在植物细胞中的治疗性蛋白质。该治疗蛋白融合于舞蹈毒素亚基B，不仅促进经粘膜转运进入循环，而且通过GM 1受体介导的内吞作用增强组织细胞摄取。我们最近已经表明，口服递送的治疗性蛋白质广泛分布在器官中，包括穿过血脑/视网膜屏障的脑和视网膜;口服递送生物包封的髓鞘碱性蛋白改善了晚期人类和小鼠阿尔茨海默病脑和视网膜中的淀粉样蛋白负荷，防止了视网膜神经节细胞的损失。因此，这种新的概念提供了治疗性蛋白质的更有效、低成本的生产和患者友好的递送，特别是向中枢神经系统的递送，这长期以来一直是一个主要的挑战。本提案的目的是在合适的动物模型中评估口服递送生物包封在植物细胞中的Ang 1 - 7和ACE 2在预防和治疗DR中的功效，并在可食用莴苣中产生和表征转质体ACE 2和Ang 1 -7表达，以推进生物包封蛋白递送方法走向临床研究。来自这些拟议研究的结果将提供关于使用口服递送基于植物叶绿体的治疗性蛋白在DR动物模型中的可行性和功效的概念验证，并为通过口服递送生物包封物ACE 2和Ang 1 -7来预防和治疗DR而启动临床试验奠定基础。