RNA sequences of AMOs administered calcium chloride induced AAA mice model

Nucleic acid medicine has been attracting attention as a new therapeutic agent for hereditary and refractory diseases that have been difficult to treat. In the development of conventional oligonucleotide therapeutics, there have been problems with stability and efficacy in vivo, but advances in modified nucleic acid technology and Drug Delivery System technology have changed this situation, and candidates that are highly effective not only after local administration but also after systemic administration are being developed. Oligonucleotide therapeutics are expected to have high specificity and efficacy similar to antibody drugs and can be produced by chemical synthesis similar to small molecule drugs. In fact, oligonucleotides are designed based on the target RNA sequence, and highly effective oligonucleotides can be obtained in a short time. In rodents, there is only one microRNA-33 (miR-33a) in the intron of sterol regulatory element binding transcription factor 2 (Srebf2), but in humans, in addition to miR-33a, there is another miR-33 (miR-33b) in the intron of SREBF1. In this study, we developed bridged nucleic acid-modified anti-microRNA oligonucleotides (AMOs) that individually target miR-33a and miR-33b, which differ by only two bases. As a result, we showed that it is possible to target aortic aneurysms and large blood vessels and elucidated its mechanism of action in detail using humanized miR-33b knock-in (KI) mice. RNA-seq analysis was performed on the aortas of miR-33b KI AAA mice treated with AMOs.