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 journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3267-3273
Number of pages7
JournalBlood
Volume121
Issue number16
DOIs
Publication statusPublished - 2013 Apr 18

Fingerprint

Transplantation Conditioning
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Interferon Type I
Stem cells
Interferons
Hematopoietic Stem Cells
Transplants
Fluorouracil
Interferon Regulatory Factor-2
Bone
Mucopolysaccharidosis VII
Therapeutics
Bone Marrow
Irradiation
Gene therapy
Hematologic Diseases
Alkylating Agents
Hematopoietic Stem Cell Transplantation
Glucuronidase
DNA

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Sato, T., Ikeda, M., Yotsumoto, S., Shimada, Y., Higuchi, T., Kobayashi, H., ... Ohteki, T. (2013). Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. Blood, 121(16), 3267-3273. https://doi.org/10.1182/blood-2012-07-443713

Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. / Sato, Taku; Ikeda, Mahoko; Yotsumoto, Satoshi; Shimada, Yohta; Higuchi, Takashi; Kobayashi, Hiroshi; Fukuda, Takahiro; Ohashi, Toya; Suda, Toshio; Ohteki, Toshiaki.

In: Blood, Vol. 121, No. 16, 18.04.2013, p. 3267-3273.

Research output: Contribution to journalArticle

Sato, T, Ikeda, M, Yotsumoto, S, Shimada, Y, Higuchi, T, Kobayashi, H, Fukuda, T, Ohashi, T, Suda, T & Ohteki, T 2013, 'Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder.', Blood, vol. 121, no. 16, pp. 3267-3273. https://doi.org/10.1182/blood-2012-07-443713
Sato T, Ikeda M, Yotsumoto S, Shimada Y, Higuchi T, Kobayashi H et al. Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. Blood. 2013 Apr 18;121(16):3267-3273. https://doi.org/10.1182/blood-2012-07-443713
Sato, Taku ; Ikeda, Mahoko ; Yotsumoto, Satoshi ; Shimada, Yohta ; Higuchi, Takashi ; Kobayashi, Hiroshi ; Fukuda, Takahiro ; Ohashi, Toya ; Suda, Toshio ; Ohteki, Toshiaki. / Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. In: Blood. 2013 ; Vol. 121, No. 16. pp. 3267-3273.
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