title: Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application.
abstract: Mismatch of human leukocyte antigens (HLA) adversely impacts the outcome of patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). This translates into the clinical requirement to timely identify suitable HLA-matched donors which in turn curtails the chances of recipients, especially those from a racial minority, to successfully undergo alloHSCT. We thus sought to broaden the existing pool of registered unrelated donors based on analysis that eliminating the expression of the HLA-A increases the chance for finding a donor matched at HLA-B, -C, and -DRB1 regardless of a patient's race. Elimination of HLA-A expression in HSC was achieved using artificial zinc finger nucleases designed to target HLA-A alleles. Significantly, these engineered HSCs maintain their ability to engraft and reconstitute hematopoiesis in immunocompromised mice. This introduced loss of HLA-A expression decreases the need to recruit large number of donors to match with potential recipients and has particular importance for patients whose HLA repertoire is under-represented in the current donor pool. Furthermore, the genetic engineering of stem cells provides a translational approach to HLA-match a limited number of third-party donors with a wide number of recipients.
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Torikai
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Tiejuan
authors.initials: T
authors.lastname: Mi
authors.affiliation: Bioinformatics Research, National Marrow Donor Program, Minneapolis, MN, U.S.A.
authors.forename: Loren
authors.initials: L
authors.lastname: Gragert
authors.affiliation: Bioinformatics Research, National Marrow Donor Program, Minneapolis, MN, U.S.A.
authors.forename: Martin
authors.initials: M
authors.lastname: Maiers
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Amer
authors.initials: A
authors.lastname: Najjar
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Sonny
authors.initials: S
authors.lastname: Ang
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Sourindra
authors.initials: S
authors.lastname: Maiti
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Dai
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Switzer
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Helen
authors.initials: H
authors.lastname: Huls
authors.affiliation: Sangamo BioSciences, Inc., Richmond, CA, U.S.A.
authors.forename: Gladys P
authors.initials: GP
authors.lastname: Dulay
authors.affiliation: Sangamo BioSciences, Inc., Richmond, CA, U.S.A.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reik
authors.affiliation: Sangamo BioSciences, Inc., Richmond, CA, U.S.A.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.affiliation: Sangamo BioSciences, Inc., Richmond, CA, U.S.A.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Holmes
authors.affiliation: Sangamo BioSciences, Inc., Richmond, CA, U.S.A.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.|Ziopharm Oncology, Inc., Boston, MA, U.S.A.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
mesh_terms: D000483:Alleles; D000818:Animals; D003851:Deoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D046148:Donor Selection / Q000941:ethics; D017353:Gene Deletion; D015870:Gene Expression; D005818:Genetic Engineering / Q000379:methods; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006297:Health Services Accessibility / Q000941:ethics; D018380:Hematopoietic Stem Cell Transplantation / Q000941:ethics / Q000208:ethnology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D051379:Mice; D044469:Racial Groups; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D016335:Zinc Fingers
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D059811:HLA-DRB1 Chains; D003851:Deoxyribonucleases