Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin.
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.
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.
Rahul
R
Palchaudhuri
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.
Borja
B
Saez
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.
Jonathan
J
Hoggatt
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.
Amir
A
Schajnovitz
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.
David B
DB
Sykes
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.
Tiffany A
TA
Tate
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.|Harvard Stem Cell Institute, 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.
Agnieszka
A
Czechowicz
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.
Youmna
Y
Kfoury
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.
Fnu
F
Ruchika
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.|Harvard Stem Cell Institute, 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.
Derrick J
DJ
Rossi
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Gregory L
GL
Verdine
Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
Michael K
MK
Mansour
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.
David T
DT
Scadden
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics / Q000276:immunology*; D005260:Female; D024861:Genetic Enhancement / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D055261:Immunogenetic Phenomena / Q000235:genetics; D000922:Immunotoxins; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054789:Ribosome Inactivating Proteins, Type 1 / Q000235:genetics* / Q000276:immunology*; D000076985:Saporins
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D000076985:Saporins