A New Lipid Nanoparticle Technology Enabling Long-acting mRNA Therapy

新型脂质纳米颗粒技术实现长效 mRNA 治疗

• 批准号: 10669826
• 负责人: Jinjun Shi
• 金额: $ 54.27万
• 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: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669826
• 关键词: Address; Adverse event; Antibodies; Apoptosis; Benchmarking; Blood; Blood Chemical Analysis; Blood Coagulation Disorders; Blood Coagulation Factor; Blood coagulation; COVID-19 vaccine; Cholesterol; Clinical; Clinical Trials; Coagulation Process; Dependovirus; Disease; Disease model; Dose; Eligibility Determination; Erythropoietin; F8 gene; FDA approved; Factor IX; Factor VIII; Formulation; Galactose; Generations; Genes; Genetic; Genetic Diseases; Half-Life; Heart; Hematocrit procedure; Hematology; Hemophilia A; Hemophilia B; Hepatocyte; Human; In Vitro; Injections; Intravenous infusion procedures; Ligands; Lipids; Lung; Measures; Mediating; Medical; Messenger RNA; Modeling; Monitor; Mus; Organ; Other Genetics; Patients; Play; Population; Production; Protein Engineering; Proteins; RNA vaccine; Recombinant Proteins; Recombinants; Replacement Therapy; Safety; Secondary to; Stains; Surface; Technology; Testing; Therapeutic; Time; Toxic effect; Validation; Work; biomaterial compatibility; enzyme replacement therapy; gene therapy; head-to-head comparison; improved; in vivo; interest; interpatient variability; lipid nanoparticle; loss of function; mRNA Expression; mRNA Translation; mRNA delivery; nanoparticle; protein expression; protein function; research clinical testing; restoration; safety study; success

ABSTRACT Recent clinical success of mRNA vaccines for COVID-19 has sparked enormous interest in mRNA therapy for a wide range of biomedical applications including protein replacement therapy. However, one unique challenge associated with mRNA therapy is dealing with the transient efficacy due to its relatively short half-life. Current nanoparticles including FDA-approved lipid nanoparticles (LNPs) could significantly improve mRNA translation efficiency, but the duration of in vivo protein expression by these mRNA NPs is generally short (limited to a few days), thus requiring frequent re-dosing. The main objective of this project is to advance a new transformative LNP technology enabling long-acting mRNA replacement therapy of genetic disorders associated with loss of function of a particular protein. In our recent studies, we developed a new generation of LNPs and performed the head-to-head comparison in vitro and in vivo to the benchmark LNP formulations composed of FDA-approved ionizable lipids. We observed a dramatic increase of the duration of model protein expression in vitro and in vivo by our new mRNA LNPs. Preliminary safety studies showed that our mRNA LNPs were well tolerated without observable adverse events in vivo. With the proof-of-concept demonstration of our long-acting mRNA LNPs, this project aims to i) further optimize the mRNA LNP technology for longer-term, high level protein expression, and ii) rigorously validate this transformative mRNA delivery platform using hemophilia A as a model disease. We expect that with successful validation in normal and hemophilia A mice, this long-acting mRNA LNP platform could be readily moved into clinical testing for hemophilia and expanded to other genetic diseases that require restoration of normal protein functions.

抽象的 mRNA疫苗在COVID-19的最新临床成功引起了对mRNA治疗的极大兴趣 广泛的生物医学应用，包括蛋白质替代疗法。但是，一个独特的挑战 与mRNA疗法相关的是，由于其半衰期相对较短，因此处理了瞬态功效。当前的 包括FDA批准的脂质纳米颗粒（LNP）在内的纳米颗粒可以显着改善mRNA翻译 效率，但是这些mRNA NP的体内蛋白表达持续时间通常很短（限于少数 几天），因此需要频繁的重新服用。该项目的主要目的是推进新的变革性 LNP技术实现了与失去遗传疾病的长效mRNA替代疗法 特定蛋白质的功能。在最近的研究中，我们开发了新一代的LNP并进行了 体外和体内的头对头比较与由FDA批准的基准LNP配方 可离子脂质。我们观察到体外和体内模型蛋白表达持续时间的持续时间显着增加 由我们的新mRNA LNP。初步安全研究表明，我们的mRNA LNP的耐受性很好 可观察到的不良事件在体内。在概念验证的证明我们的长效mRNA LNP中， 项目旨在i）进一步优化mRNA LNP技术，以进行长期，高水平的蛋白质表达和 ii）使用血友病A作为模型疾病，严格验证该变换性mRNA递送平台。我们 期望通过在正常和血友病A小鼠中成功验证，这个长效的mRNA LNP平台 可以很容易地将其转移到血友病的临床测试中，并扩展到其他需要的遗传疾病 恢复正常蛋白质功能。