title: Pigtailed macaques as a model to study long-term safety of lentivirus vector-mediated gene therapy for hemoglobinopathies.
abstract: Safely achieving long-term engraftment of genetically modified hematopoietic stem cells (HSCs) that maintain therapeutic transgene expression is the benchmark for successful application of gene therapy for hemoglobinopathies. We used the pigtailed macaque HSC transplantation model to ascertain the long-term safety and stability of a γ-globin lentivirus vector. We observed stable gene-modified cells and fetal hemoglobin expression for 3 years. Retrovirus integration site (RIS) analysis spanning 6 months to 3.1 years revealed vastly disparate integration profiles, and dynamic fluctuation of hematopoietic contribution from different gene-modified HSC clones without evidence for clonal dominance. There were no perturbations of the global gene-expression profile or expression of genes within a 300 kb region of RIS, including genes surrounding the most abundantly marked clones. Overall, a 3-year long follow-up revealed no evidence of genotoxicity of the γ-globin lentivirus vector with multilineage polyclonal hematopoiesis, and HSC clonal fluctuations that were not associated with transcriptome dysregulation.
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle, Washington, USA ; University of Washington Medical School , Seattle, Washington, USA.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio, USA.
authors.forename: Paritha I
authors.initials: PI
authors.lastname: Arumugam
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Burtner
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio, USA.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Fox
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Beard
authors.affiliation: Divisions of Human Genetics and Bioinformatics, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Dexheimer
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle, Washington, USA ; University of Washington Medical School , Seattle, Washington, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Adair
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio, USA.
authors.forename: Punam
authors.initials: P
authors.lastname: Malik