Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder

Blood. 2013 Apr 18;121(16):3267-73. doi: 10.1182/blood-2012-07-443713. Epub 2013 Feb 14.


Hematopoietic stem cell (HSC) gene therapy is a potentially curative treatment modality for monogenic hematological diseases and storage disorders. It is necessary, however, to establish pre-bone marrow (BM) transplant conditioning regimens that minimize DNA damage and toxicity. Type I interferon (IFN) signaling activates quiescent HSCs and enables them to be sensitive to 5-fluorouracil (FU)-mediated cytotoxicity, thus implying a molecular basis for improving HSC transplant outcomes. Here we show that type I IFN preconditioning, without irradiation or DNA alkylating agents, significantly enhanced the HSC engraftment efficiency in wild-type (WT) recipient mice. The importance of active type I IFN signaling in HSC recipients was further demonstrated using mice lacking IFN regulatory factor 2 (IRF2), a transcriptional suppressor of type I IFN signaling. In both WT and Irf2(-/-) recipients, active type I IFN signaling greatly enhanced the sensitivity to 5-FU or low-dose irradiation of HSCs. Importantly, IFN-based pre-BM transplant conditioning was also applicable to the treatment of Sly syndrome, a congenital storage disorder with β-glucuronidase deficiency, in which it restored enzyme expression at the HSC level and reciprocally reduced pathological glycosaminoglycan storage. Our findings suggest type I IFN-based preconditioning, combined with HSC transplantation, as a novel nongenotoxic treatment of some congenital diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Bone Marrow Transplantation / methods
  • Fluorouracil / therapeutic use
  • Gene Deletion
  • Hematopoietic Stem Cell Transplantation / methods*
  • Interferon Regulatory Factor-2 / genetics
  • Interferon Type I / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Mucopolysaccharidosis VII / surgery
  • Mucopolysaccharidosis VII / therapy*
  • Transplantation Conditioning / methods*


  • Antineoplastic Agents
  • Interferon Regulatory Factor-2
  • Interferon Type I
  • Fluorouracil