Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure

Clara T. Nicolas, Robert A. Kaiser, Raymond D. Hickey, Kari L. Allen, Zeji Du, Caitlin J. VanLith, Rebekah M. Guthman, Bruce Amiot, Lukkana Suksanpaisan, Bing Han, Maria Giovanna Francipane, Amin Cheikhi, Huailei Jiang, Aditya Bansal, Mukesh K. Pandey, Ishan Garg, Val Lowe, Aditya Bhagwate, Daniel O'Brien, Jean Pierre A. KocherTimothy R. DeGrado, Scott L. Nyberg, Eric Lagasse, Joseph B. Lillegard

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)738-750
Number of pages13
JournalMolecular Therapy - Methods and Clinical Development
Volume18
DOIs
StatePublished - Sep 11 2020

Keywords

  • gene therapy
  • hepatocyte transplantation
  • lentiviral
  • liver failure
  • lymph node
  • metabolic liver disease
  • tyrosinemia

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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