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疾病（例如，血友病）的基石 通过使用重组蛋白或重组工程的重组蛋白的功能降低特定蛋白质的功能 蛋白质。但是，大多数蛋白质疗法的循环寿命短，因此需要频繁的侵入性 输注以保持其治疗功效。例如，对血友病A的最常见治疗 由于血液凝结因子VIII（FVIII）的缺乏，是浓缩液的替代品，与之相关 繁琐的频繁静脉输注。为了满足未满足的血友病的医疗需求 该项目的目的是开发耐用蛋白质的非侵入性口服mRNA递送纳米文化 需要不经常给药的替代疗法。合成mRNA已显示出巨大的生物医学潜力 应用，MRNA疫苗已经临床批准了COVID-19。各种交货策略 开发以改善mRNA翻译；但是，mRNA疗法的持续挑战正在管理 由于其相对较短的半衰期以及口服mRNA递送引起的瞬时功效仍然难以捉摸。在我的上一个 工作，我已经确定了一个独特的聚（zwitterion）基于脂质的胶束平台，可以越过肠上皮 屏障并导致生物分子（例如胰岛素）的口服生物利用度非常有效。最近，我也有 发现了一种新型的可离子脂质，可以扩展mRNA介导的蛋白表达的持续时间。在 这个F32项目，我建议结合上皮上皮的poly（zwitterion）-lipids和独特的电离 脂质开发用于口服，耐用的替代疗法的创新mRNA输送平台 疾病。在AIM 1中，我将合成新的poly（zwitterion） - 脂肪和可离子脂质，并生成一系列新的 mRNA脂质纳米颗粒（LNP），并系统地研究其对口腔胞症的影响和 蛋白质表达在体外和体内的耐用性。在AIM 2中，我们将为口服选择顶级的LNP 递送FVIII mRNA并评估健康和血友病模型中的FVIII mRNA纳米疗法。 随着该项目的成功完成，我们希望口服耐用的mRNA交付策略将提供 对血友病和其他出血疾病的更有效，更健壮的疗法。