Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Japan Science and Technology Agency (JST) Fusion Oriented Research for Disruptive Science and Technology (FOREST) Program, Kawaguchi, Japan.
Handb Exp Pharmacol. 2024;284:329-339. doi: 10.1007/164_2023_650.
The approval of mRNA-containing lipid nanoparticles (LNPs) for use in a vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the clinical utility of RNA-loaded nanocapsules has stimulated a rapid acceleration in research in this area. The development of mRNA-containing LNP vaccines has been rapid, not only because of regulatory adjustments, but also to the advances made in nucleic acid delivery as the result of efforts by many basic researchers. RNA functions, not only in the nucleus and cytoplasm, but also in mitochondria, which have their own genomic apparatus. Mitochondrial diseases caused by mutations or defects in the mitochondrial genome, mitochondrial DNA (mtDNA) are intractable and are mainly treated symptomatically, but gene therapy as a fundamental treatment is expected to soon be a reality. To realize this therapy, a drug delivery system (DDS) that delivers nucleic acids including RNA to mitochondria is required, but efforts in this area have been limited compared to research targeting the nucleus and cytoplasm. This contribution provides an overview of mitochondria-targeted gene therapy strategies and discusses studies that have attempted to validate mitochondria-targeted RNA delivery therapies. We also present the results of 'RNA delivery to mitochondria' based on the use of our mitochondria-targeted DDS (MITO-Porter) that was developed in our laboratory.
mRNA 脂质纳米颗粒 (LNPs) 用于 SARS-CoV-2 疫苗的批准以及载 RNA 的纳米胶囊的临床应用，刺激了该领域研究的快速加速。mRNA 脂质纳米颗粒疫苗的发展非常迅速，不仅是因为监管调整，还因为许多基础研究人员的努力推动了核酸传递方面的进展。RNA 的功能不仅在细胞核和细胞质中，而且在具有自身基因组装置的线粒体中。由线粒体基因组、线粒体 DNA (mtDNA) 的突变或缺陷引起的线粒体疾病是难治性的，主要是对症治疗，但作为根本治疗的基因治疗有望很快成为现实。为了实现这种治疗，需要一种将包括 RNA 在内的核酸递送到线粒体的药物递送系统 (DDS)，但与针对细胞核和细胞质的研究相比，该领域的努力受到限制。本综述概述了线粒体靶向基因治疗策略，并讨论了尝试验证线粒体靶向 RNA 递药疗法的研究。我们还根据我们实验室开发的线粒体靶向 DDS（MITO-Porter）进行的“线粒体 RNA 递药”的结果。
