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Nat Biotechnol. 2016 Jul;34(7):738-45. doi: 10.1038/nbt.3584. Epub 2016 Jun 6.

Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin.

Palchaudhuri R1,2,3,4, Saez B1,2,3, Hoggatt J1,2,3, Schajnovitz A1,2,3, Sykes DB1,2,3, Tate TA1,2,3, Czechowicz A1,3,5,6,7, Kfoury Y1,2,3, Ruchika F1,2,3, Rossi DJ1,3,5,6, Verdine GL1,3,4, Mansour MK8, Scadden DT1,2,3.

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Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.


Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45-saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45-SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity. This non-genotoxic conditioning method may provide an attractive alternative to current conditioning regimens for HSCT in the treatment of non-malignant blood diseases.

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Conflict of interest statement

The authors declare competing financial interests: details are available in the online version of the paper.

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