Therapeutic Transgenes Thwarted by Suppressive MicroRNAs in Induced Pacemaker Cell Study

For a paper in Cell Reports Medicine, a team from Cedars-Sinai Medical Center's Smidt Heart Institute describes microRNAs that dampen translation of the human T-box transcription factor 18 (TBX18) — and its ability to boost pacing activity in the heart — after delivery with a chemically modified messenger RNA (CMmRNA) system. With small RNA sequencing, the researchers saw higher-than-usual expression of the miR-1-3p and miR-1b miRNAs in cells transfected with CMmTBX18, which appeared to dial down CMmTBX18 expression in heart cells or left ventricle heart tissue from atrioventricularly blocked rats. On the other hand, they report, TBX18 translation and heart pacing was enhanced when the CMmRNA containing TBX18 was delivered with specialized anti-miR antagomir oligonucleotides targeting the apparently suppressive miR-1-3p and miR-1b miRNAs. From these and other findings, the authors argue that cells "resist translation of CMmRNA therapeutic transgenes by upregulating suppressive miRs." Consequently, they say, the results "have conceptual as well as practical value: we not only identify a homeostatic mechanism whereby cells use miRs to resist CMmRNA transgene expression but also pinpoint ways to improve the efficiency of CMmmRNA therapeutics," they suggest.