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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的最近针对 COVID-19 的 mRNA 疫苗在临床上取得的成功引发了人们对 mRNA 疗法的巨大兴趣广泛的生物医学应用，包括蛋白质替代疗法。然而，一项独特的挑战与 mRNA 疗法相关的问题是由于其半衰期相对较短，因此疗效短暂。当前的纳米颗粒，包括 FDA 批准的脂质纳米颗粒 (LNP) 可以显着改善 mRNA 翻译效率，但这些 mRNA NP 体内蛋白质表达的持续时间通常很短（仅限于少数天），因此需要频繁重新给药。该项目的主要目标是推进新的变革 LNP 技术能够对与基因缺失相关的遗传性疾病进行长效 mRNA 替代疗法特定蛋白质的功能。在我们最近的研究中，我们开发了新一代 LNP 并进行了与 FDA 批准的 LNP 基准配方进行体外和体内头对头比较可电离的脂质。我们观察到模型蛋白表达的体外和体内持续时间显着增加通过我们新的 mRNA LNP。初步安全性研究表明，我们的 mRNA LNP 具有良好的耐受性，无需体内可观察到的不良事件。通过我们的长效 mRNA LNP 的概念验证演示，这项目的目标是 i) 进一步优化 mRNA LNP 技术以实现长期、高水平的蛋白质表达，以及 ii) 使用 A 型血友病作为模型疾病严格验证这一变革性 mRNA 传递平台。我们预计这种长效 mRNA LNP 平台能够在正常小鼠和 A 型血友病小鼠中获得成功验证可以很容易地进入血友病的临床测试，并扩展到需要的其他遗传疾病恢复正常的蛋白质功能。