Development of novel nucleic acid therapy aimed to directly controlling liver fibrosis

Currently, no drugs directly treat liver fibrosis. Previously, we showed that treatment with miR-29a-3p improved liver fibrosis in a mouse model. To investigate the effectiveness of nucleic acid therapy at a lower dose, a modified nucleic acid was prepared based on miR-29a-3p. The original microRNA was changed to an RNA–DNA hybrid structure: the 2' position of the RNA was modified with a fluorine base, and locked nucleic acid and phosphorothioate were crosslinked (hereafter modified nucleic acid). In a mouse model of chronic liver disease treated with carbon tetrachloride (CCl4), the inhibitory effect on liver fibrosis was evaluated with the oral administration of the modified nucleic acid. The modified nucleic acid was detected in the liver and gastrointestinal tract within 15 min of oral administration. After 5 weeks of stimulation with CCl4, oral administration of the modified nucleic acid for 2 weeks improved liver fibrosis; CCl4 stimulation was continued during this period as well. This treatment also suppressed the worsening of liver fibrosis. We have developed a method to improve liver fibrosis orally using nuclease-resistant nucleic acids without using drug delivery system. This method may be used as a new treatment for inhibiting the progression of liver fibrosis. [Display omitted] Murakami and colleagues found that nucleic acids that control multiple targets improve liver fibrosis. Nucleic acids can become nuclease resistant by changing their structure and modification and can suppress target genes in vivo. This novel drug can be administered orally and has demonstrated potential in improving liver fibrosis.