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.

抽象的 蛋白质替代疗法一直是治疗遗传性疾病（例如血友病）的基石。 通过使用重组蛋白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较短，因此需要频繁的侵入性治疗 输注以维持其治疗效果。例如，A型血友病最常见的治疗方法是 缺乏凝血因子 VIII (FVIII) 是因子浓缩物替代，这与 频繁静脉输注造成负担。为了解决血友病未得到满足的医疗需求，主要 该项目的目标是开发一种用于持久蛋白质的非侵入性口服 mRNA 递送纳米平台 需要不频繁给药的替代疗法。合成mRNA在生物医学领域显示出巨大潜力 应用，mRNA 疫苗已获得临床批准用于治疗 COVID-19。多种交付策略 被开发用于改善 mRNA 翻译；然而，mRNA 疗法的一个持续挑战是管理 由于其相对较短的半衰期和口服 mRNA 传递而导致的短暂疗效仍然难以捉摸。在我之前的 在工作中，我发现了一种独特的基于聚（两性离子）脂质的胶束平台，可以穿过肠上皮 屏障并导致生物分子（例如胰岛素）具有非常有效的口服生物利用度。最近我也 发现了一种新型可电离脂质，可以延长 mRNA 介导的蛋白质表达的持续时间。在 在这个 F32 项目中，我建议将上皮细胞交叉的聚（两性离子）脂质和独特的可电离 脂质开发创新的 mRNA 递送平台，用于口服、持久的出血替代疗法 失调。在目标 1 中，我将合成新的聚（两性离子）脂质和可电离脂质，并生成一系列新的 mRNA 脂质纳米粒子 (LNP)，并系统地研究它们对口腔转胞吞作用和 体外和体内蛋白质表达的持久性。在目标 2 中，我们将选择表现最好的 LNP 进行口服 FVIII mRNA 的递送并在健康和血友病小鼠模型中评估 FVIII mRNA 纳米疗法。 随着该项目的成功完成，我们预计口服持久 mRNA 递送策略将提供 对血友病和其他出血性疾病更有效、更稳健的治疗方法。