mRNA therapeutics for liver diseases: HNF4A mRNA delivery via lipid nanoparticles attenuates liver fibrosis in preclinical models.

Messenger RNA (mRNA)-based drug technologies are expeditiously reaching the clinic and bear the capacity to benefit millions of individuals globally. However, therapeutic targeting of injuries that demand transient restoration of proteins by mRNA delivery requires more in-depth analyses. In this study, we investigated therapeutic applicability of mRNA delivery in liver fibrosis and cirrhosis, which causes millions of fatalities, annually. Here, we envisioned to demonstrate the therapeutic utility of the human transcription factor, hepatocyte nuclear factor alpha (HNF4A) encoding mRNA, in chronically injured mouse liver leading to fibrosis and cirrhosis. We demonstrated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and examined the inhibition of liver fibrosis and cirrhosis in numerous murine models, by administering hepatocyte-targeted lipid nanoparticles (LNP) encapsulating HNF4A mRNA. The potential mechanisms of HNF4A mRNA in attenuation of liver fibrosis were discovered by performing microarray-based gene expression profiling, single cell RNA sequencing, and chromatin immunoprecipitation. Primary liver cells and human liver buds were used for functional validation.

Expression of HNF4A mRNA restored metabolic functions of fibrotic primary human hepatocytes in vitro. Repeated in vivo administration of HNF4A mRNA encapsulated-LNP triggered a strong suppression of fibrogenesis in four independent murine models of hepatotoxin- and cholestasis-induced liver fibrosis. We identified that HNF4A targets paraoxonase 1, which mediates HFF4A-directed inhibition of liver fibrosis by regulating liver macrophages and hepatic stellate cells.

Taken together, our results provide the first direct pre-clinical evidence that HNF4A mRNA therapeutics would be a promising strategy for the treatment of liver fibrosis.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022