title: Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder.
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.
authors: Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-5810, Japan.
authors: Taku
authors: T
authors: Sato
authors: Mahoko
authors: M
authors: Ikeda
authors: Satoshi
authors: S
authors: Yotsumoto
authors: Yohta
authors: Y
authors: Shimada
authors: Takashi
authors: T
authors: Higuchi
authors: Hiroshi
authors: H
authors: Kobayashi
authors: Takahiro
authors: T
authors: Fukuda
authors: Toya
authors: T
authors: Ohashi
authors: Toshio
authors: T
authors: Suda
authors: Toshiaki
authors: T
authors: Ohteki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000379:methods; D005472:Fluorouracil / Q000627:therapeutic use; D017353:Gene Deletion; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D050836:Interferon Regulatory Factor-2 / Q000235:genetics; D007370:Interferon Type I / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D016538:Mucopolysaccharidosis VII / Q000601:surgery / Q000628:therapy*; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D050836:Interferon Regulatory Factor-2; D007370:Interferon Type I; D005472:Fluorouracil