| First Author | Sato T | Year | 2013 |
| Journal | Blood | Volume | 121 |
| Issue | 16 | Pages | 3267-73 |
| PubMed ID | 23412092 | Mgi Jnum | J:196707 |
| Mgi Id | MGI:5489046 | Doi | 10.1182/blood-2012-07-443713 |
| Citation | Sato T, et al. (2013) Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. Blood 121(16):3267-73 |
| abstractText | 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 beta-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. |
