Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA

Fatima Rizvi, Elissa Everton, Anna R. Smith, Hua Liu, Elizabeth Osota, Mitchell Beattie, Ying Tam, Norbert Pardi, Drew Weissman and Valerie Gouon-Evans ()
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Fatima Rizvi: Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center
Elissa Everton: Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center
Anna R. Smith: Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center
Hua Liu: Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center
Elizabeth Osota: Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center
Mitchell Beattie: Acuitas Therapeutics
Ying Tam: Acuitas Therapeutics
Norbert Pardi: Department of Medicine, University of Pennsylvania
Drew Weissman: Department of Medicine, University of Pennsylvania
Valerie Gouon-Evans: Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.

Date: 2021
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DOI: 10.1038/s41467-021-20903-3

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