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Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice

Anna R. Smith, Fatima Rizvi, Elissa Everton, Anisah Adeagbo, Susan Wu, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman and Valerie Gouon-Evans ()
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Anna R. Smith: Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center
Fatima Rizvi: Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center
Elissa Everton: Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center
Anisah Adeagbo: Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center
Susan Wu: Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center
Ying Tam: Acuitas Therapeutics
Hiromi Muramatsu: University of Pennsylvania Perelman School of Medicine
Norbert Pardi: University of Pennsylvania Perelman School of Medicine
Drew Weissman: University of Pennsylvania Perelman School of Medicine
Valerie Gouon-Evans: Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two male mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.

Date: 2024
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DOI: 10.1038/s41467-024-49332-8

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