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 蛋白质替代疗法已经成为治疗遗传疾病（例如，血友病）， 通过使用重组蛋白质或重组工程化的蛋白质来降低特定蛋白质的功能 proteins.然而，大多数蛋白质治疗剂具有短的循环寿命，因此需要频繁的侵入性治疗。 输注以维持其治疗功效。例如，血友病A最常见的治疗方法是 凝血因子VIII（FVIII）缺乏是因子浓缩物替代，这与 频繁静脉输液的负担为了解决血友病未得到满足的医疗需求， 本项目的目的是开发一种非侵入性的口服mRNA递送纳米平台，用于持久的蛋白质 需要不频繁给药的替代疗法。人工合成的mRNA在生物医学领域显示出巨大的潜力。 mRNA疫苗已经获得临床批准用于COVID-19。各种交付战略 已经开发了改善mRNA翻译;然而，mRNA治疗的持续挑战是管理 由于其相对短的半衰期和口服mRNA递送而产生的瞬时功效仍然难以捉摸。在我以前的 工作，我已经确定了一个独特的聚（zwitzerland）-脂质为基础的胶束平台，可以通过肠上皮细胞 屏障并导致生物分子如胰岛素的非常有效的口服生物利用度。最近，我也 发现了一种新型的可电离脂质，可以延长mRNA介导的蛋白质表达的持续时间。在 这个F32项目，我建议将联合收割机结合上皮交叉聚（两性）脂质和独特的可电离的 脂质开发一种创新的mRNA递送平台，用于口服，持久的出血替代疗法 紊乱目的一是合成新型聚两性离子脂质和可离子化脂质， mRNA脂质纳米粒（LNPs），并系统地研究其对口腔转胞吞作用和细胞增殖的影响。 体外和体内蛋白表达的持久性。在目标2中，我们将选择性能最佳的口服LNP 在健康和血友病小鼠模型中递送FVIII mRNA并评估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 一种更有效和更强大的治疗血友病和其他出血性疾病的方法。