@article{c7078dc8b942454d953273a3bf8cb9f6,
title = "Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure",
abstract = "The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced ex vivo with a lentiviral vector carrying the pig Fah gene and transplanted into mesenteric lymph nodes. Hepatocytes showed early (6 h) and durable (8 months) engraftment in lymph nodes, with reproduction of vascular and hepatic microarchitecture. Subsequently, hepatocytes migrated to and repopulated the native diseased liver. The corrected cells generated sufficient liver mass to clinically ameliorate the acute liver failure and HT1 disease as early as 97 days post-transplantation. Integration site analysis defined the corrected hepatocytes in the liver as a subpopulation of hepatocytes from lymph nodes, indicating that the lymph nodes served as a source for healthy hepatocytes to repopulate a diseased liver. Therefore, ectopic transplantation of healthy hepatocytes cures this pig model of liver failure and presents a promising approach for the development of cures for liver disease in patients.",
keywords = "gene therapy, hepatocyte transplantation, lentiviral, liver failure, lymph node, metabolic liver disease, tyrosinemia",
author = "Nicolas, {Clara T.} and Kaiser, {Robert A.} and Hickey, {Raymond D.} and Allen, {Kari L.} and Zeji Du and VanLith, {Caitlin J.} and Guthman, {Rebekah M.} and Bruce Amiot and Lukkana Suksanpaisan and Bing Han and Francipane, {Maria Giovanna} and Amin Cheikhi and Huailei Jiang and Aditya Bansal and Pandey, {Mukesh K.} and Ishan Garg and Val Lowe and Aditya Bhagwate and Daniel O'Brien and Kocher, {Jean Pierre A.} and DeGrado, {Timothy R.} and Nyberg, {Scott L.} and Eric Lagasse and Lillegard, {Joseph B.}",
note = "Funding Information: We thank T. Wyman and L. Filzen for large-animal PET imaging support; L. Gross and L. Acosta for histology support; S. Krage and J. Pederson for surgical support; L. Hillin for animal support; and P. Steiner for graphical support. Funding for the project was received from NIH (K01 DK106056); Mayo CTSA (grant UL1TR000135); Regenerative Medicine Minnesota (RMM 101617TR002); Children's Minnesota Foundation; NIH (R01 DK114282 to B.H. and E.L.); Commonwealth of Pennsylvania (SAP4100073573 to M.G.F. and E.L.); and Ri.MED Foundation (to M.G.F.). Funding Information: We thank T. Wyman and L. Filzen for large-animal PET imaging support; L. Gross and L. Acosta for histology support; S. Krage and J. Pederson for surgical support; L. Hillin for animal support; and P. Steiner for graphical support. Funding for the project was received from NIH ( K01 DK106056 ); Mayo CTSA (grant UL1TR000135 ); Regenerative Medicine Minnesota ( RMM 101617TR002 ); Children{\textquoteright}s Minnesota Foundation ; NIH ( R01 DK114282 to B.H. and E.L.); Commonwealth of Pennsylvania ( SAP4100073573 to M.G.F. and E.L.); and Ri.MED Foundation (to M.G.F.). Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = sep,
day = "11",
doi = "10.1016/j.omtm.2020.07.009",
language = "English (US)",
volume = "18",
pages = "738--750",
journal = "Molecular Therapy - Methods and Clinical Development",
issn = "2329-0501",
publisher = "Nature Publishing Group",
}