Oral mRNA Nanotherapy for Bleeding Disorder

口服 mRNA 纳米疗法治疗出血性疾病

• 批准号: 10750040
• 负责人: Xiangfei Han
• 金额: $ 6.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750040
• 关键词: Address; Amino Acid Transporter; Biodistribution; Biological Availability; Blood Chemical Analysis; Blood Coagulation Disorders; Blood Coagulation Factor; Blood coagulation; COVID-19; Circulation; Clinic; Clinical; Coagulation Process; Development; Diffusion; Doctor of Philosophy; Dose; Epithelium; Erythropoietin; Evaluation; Factor VIII; Formulation; Generations; Genetic Diseases; Goals; Half-Life; Hematocrit procedure; Hematology; Hemophilia A; Hepatocyte; Human; In Vitro; Infusion procedures; Insulin; Intravenous infusion procedures; Laboratories; Lead; Light; Lipid Chemistry; Lipids; Liver; Measures; Mediating; Medical; Messenger RNA; Micelles; Modality; Modeling; Monitor; Mucous body substance; Mus; Nanotechnology; Nature; Oral; Oral Administration; Organ; Patients; Pattern; Permeability; Property; Protein Engineering; Protein Overexpression; Proteins; Protons; RNA delivery; RNA vaccine; Recombinant Proteins; Recombinants; Replacement Therapy; Reporting; Route; Safety; Series; Stains; Testing; Therapeutic; Tight Junctions; Time; Training; Translations; Transportation; Treatment Efficacy; Work; absorption; biomaterial compatibility; common treatment; compliance behavior; cytotoxicity; enzyme replacement therapy; improved; in vitro activity; in vivo; injection/infusion; innovation; intestinal epithelium; lipid nanoparticle; mRNA Translation; mRNA delivery; mouse model; nanoparticle delivery; nanotechnology platform; nanotherapy; novel; novel therapeutics; protein expression; screening; side effect; therapeutic protein; transcytosis

ABSTRACT Protein replacement therapy has been a cornerstone in treating genetic diseases (e.g., hemophilia) with loss or reduction of the function of a particular protein, by using recombinant proteins or recombinant engineered proteins. However, most protein therapeutics have short circulation lives, and thus require frequent invasive infusion to maintain their therapeutic efficacy. For example, the most common treatment for hemophilia A caused by a deficiency of blood clotting factor VIII (FVIII) is factor concentrate replacement, which is associated with burdensome frequent intravenous infusion. To address the unmet medical need of hemophilia, the major objective of this project is to develop a non-invasive oral mRNA delivery nanoplatform for durable protein replacement therapy requiring infrequent dosing. Synthetic mRNA has shown enormous potential for biomedical applications, with mRNA vaccines already clinically approved for COVID-19. Various delivery strategies have been developed to improve mRNA translation; however, an ongoing challenge of mRNA therapy is managing the transient efficacy due to its relatively short half-life, and oral mRNA delivery remains elusive. In my previous work, I have identified a unique poly(zwitterion)-lipid-based micelle platform that can cross the intestinal epithelial barrier and lead to a very potent oral bioavailability of biomolecules such as insulin. Recently, I have also discovered a new type of ionizable lipids that can extend the duration of mRNA-mediated protein expression. In this F32 project, I propose to combine the epithelium-crossing poly(zwitterion)-lipids and the unique ionizable lipids to develop an innovative mRNA delivery platform for oral, durable replacement therapy of bleeding disorders. In Aim 1, I will synthesize new poly(zwitterion)-lipids and ionizable lipids and generate a series of new mRNA lipid nanoparticles (LNPs), and systematically investigate their effects on oral transcytosis and the durability of protein expression in vitro and in vivo. In Aim 2, we will select the top-performing LNPs for oral delivery of FVIII mRNA and evaluate the FVIII mRNA nanotherapy in healthy and hemophilia mouse models. With the successful completion of this project, we expect that the oral durable mRNA delivery strategy will provide a more effective and robust therapy for hemophilia and other bleeding disorders.

摘要 蛋白质替代疗法一直是治疗遗传性疾病(如血友病)的基石。 通过使用重组蛋白质或重组工程来降低特定蛋白质的功能 蛋白质。然而，大多数蛋白质疗法的循环寿命短，因此需要频繁的侵入性治疗。 输液以维持其治疗效果。例如，血友病A最常见的治疗方法是 凝血因子VIII(FVIII)是凝血因子的替代，与凝血因子的缺乏有关 繁重的频繁静脉输液。为了解决血友病未得到满足的医疗需求，主要的 本项目的目标是开发一种非侵入性口服信使核糖核酸传递耐久蛋白的纳米平台 需要很少用药的替代疗法。人工合成的信使核糖核酸在生物医学方面显示出巨大的潜力 应用，信使核糖核酸疫苗已经被临床批准用于新冠肺炎。各种交付策略都有 被开发来改善信使核糖核酸的翻译；然而，信使核糖核酸治疗的一个持续的挑战是管理 由于其相对较短的半衰期和口服信使核糖核酸的传递，其短暂的疗效仍然难以捉摸。在我之前的 工作中，我发现了一种独特的聚(两性离子)-基于脂质的胶束平台，它可以穿过肠道上皮 并导致胰岛素等生物分子具有非常强的口服生物利用度。最近，我也 发现了一种新型的可电离脂质，可以延长信使核糖核酸介导的蛋白质表达的持续时间。在……里面 在这个F32项目中，我建议将跨越上皮的聚(两性)脂和独特的可电离 Lipids将开发一种创新的信使核糖核酸传递平台，用于口服、持久的止血替代疗法 精神错乱。在目标1中，我将合成新的两性离子脂类和可电离类脂，并生成一系列新的 信使核糖核酸脂纳米粒(LNPs)，并系统地研究了它们对口腔转胞作用的影响和 蛋白质在体外和体内表达的持久性。在目标2中，我们将选出表现最好的LNPs进行口语 在健康和血友病小鼠模型中传递FVIII信使核糖核酸并评价FVIII信使核糖核酸纳米治疗。 随着这个项目的成功完成，我们预计口服持久信使核糖核酸传递策略将提供 对血友病和其他出血性疾病更有效和更有力的治疗方法。