小W
(2024-04-30 23:51):
#paper doi:10.1038/s41573-023-00859-3 Strategies to reduce the risks of mRNA drug and vaccine toxicity 本文是一篇介绍RNA药物在心血管疾病中开发应用的文章。介绍了 AZD8601(VEGF-A mRNA Moderna) 在血运重建的临床试验进展,miR 组合(miR-1、miR133等)相比转录因子方法将成纤维细胞重编程为心肌细胞的优势,CDR132L(antimiR miR-132-3p) 可减少心脏纤维化并预防心力衰竭,zilebesiran (siRNA 肾素-血管紧张素-醛固酮系统)单次注射可在半年内控制高血压,Inclisiran (siRNA 靶向PCSK9)用于治疗动脉粥样硬化性心血管随着疾病和杂合子家族性高胆固醇血症等RNA药物开发逻辑和优劣势。随着现代社会心血管疾病诱因增加以及RNA药物开发体系的完善,RNA药物会成为应对心血管疾病的一个思路。
Strategies to reduce the risks of mRNA drug and vaccine toxicity
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Abstract:
mRNA formulated with lipid nanoparticles is a transformative technology that has enabled the rapid development and administration of billions of coronavirus disease 2019 (COVID-19) vaccine doses worldwide. However, avoiding unacceptable toxicity with mRNA drugs and vaccines presents challenges. Lipid nanoparticle structural components, production methods, route of administration and proteins produced from complexed mRNAs all present toxicity concerns. Here, we discuss these concerns, specifically how cell tropism and tissue distribution of mRNA and lipid nanoparticles can lead to toxicity, and their possible reactogenicity. We focus on adverse events from mRNA applications for protein replacement and gene editing therapies as well as vaccines, tracing common biochemical and cellular pathways. The potential and limitations of existing models and tools used to screen for on-target efficacy and de-risk off-target toxicity, including in vivo and next-generation in vitro models, are also discussed.
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