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

Taku Sato, Mahoko Ikeda, Satoshi Yotsumoto, Yohta Shimada, Takashi Higuchi, Hiroshi Kobayashi, Takahiro Fukuda, Toya Ohashi, Toshio Suda, Toshiaki Ohteki

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


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 Irf22/2 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 b-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.

Original languageEnglish
Pages (from-to)3267-3273
Number of pages7
Issue number16
Publication statusPublished - 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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