Autologous and Heterologous Cell Therapy for Hemophilia B toward Functional Restoration of Factor IX

Cell Rep. 2018 May 1;23(5):1565-1580. doi: 10.1016/j.celrep.2018.03.121.

Abstract

Hemophilia B is an ideal target for gene- and cell-based therapies because of its monogenic nature and broad therapeutic index. Here, we demonstrate the use of cell therapy as a potential long-term cure for hemophilia B in our FIX-deficient mouse model. We show that transplanted, cryopreserved, cadaveric human hepatocytes remain functional for more than a year and secrete FIX at therapeutic levels. Hepatocytes from different sources (companies and donors) perform comparably in curing the bleeding defect. We also generated induced pluripotent stem cells (iPSCs) from two hemophilia B patients and corrected the disease-causing mutations in them by two different approaches (mutation specific and universal). These corrected iPSCs were differentiated into hepatocyte-like cells (HLCs) and transplanted into hemophilic mice. We demonstrate these iPSC-HLCs to be viable and functional in mouse models for 9-12 months. This study aims to establish the use of cells from autologous and heterologous sources to treat hemophilia B.

Keywords: autologous cell therapy; cell therapy; hemophilia; heterologous cell therapy; iPSc derived hepatocyte-like cells; liver; monogenic liver diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Transplantation*
  • Disease Models, Animal
  • Factor IX / metabolism*
  • Hemophilia B / genetics
  • Hemophilia B / metabolism
  • Hemophilia B / pathology
  • Hemophilia B / therapy*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatocytes / transplantation*
  • Heterografts
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Induced Pluripotent Stem Cells / transplantation*
  • Mice
  • Mice, Knockout

Substances

  • Factor IX