title: Stem cell factor-displaying simian immunodeficiency viral vectors together with a low conditioning regimen allow for long-term engraftment of gene-marked autologous hematopoietic stem cells in macaques.
abstract: Although clinical benefits have been reported in several human hematopoietic gene therapy trials, a remaining important goal is the transition to nonmyeloablative pretransplantation conditioning to decrease toxicity. Previous attempts at reduced intensity conditioning in nonhuman primates have resulted in only temporary vector marking of autologous blood cells or their persistence at low levels, well below the thresholds for clinical efficacy. In addition, we reasoned that lentiviral vector particles displaying cytokines at their surface have the potential to preserve stem cell fitness better than current ex vivo transduction protocols, which involve exposure to cytokine overstimulation. Here we show that the classically nonmyeloablative agent fludarabine (30 mg/m(2)/day for 3 days) together with low-level total body irradiation (2 Gy) and the use of a stem cell factor-displaying simian immunodeficiency virus-based vector, resulted in sustained, single-copy vector marking of autologous blood cells in two macaques over 3 years posttransplantation at levels averaging 1% of all lineages. This percentage is within the range of anticipated efficacy levels for hemophilia and related diseases and forms a basis for further improvement.
authors.affiliation: Université de Lyon, F69000, Lyon, France. els.verhoeyen@ens-lyon.fr
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.forename: Francis
authors.initials: F
authors.lastname: Relouzat
authors.forename: Marie
authors.initials: M
authors.lastname: Cambot
authors.forename: Caroline
authors.initials: C
authors.lastname: Costa
authors.forename: Didier
authors.initials: D
authors.lastname: Nègre
authors.forename: Faézeh
authors.initials: F
authors.lastname: Legrand
authors.forename: Christophe
authors.initials: C
authors.lastname: Joubert
authors.forename: Roger
authors.initials: R
authors.lastname: Le Grand
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.forename: Anne
authors.initials: A
authors.lastname: Dubart-Kupperschmitt
authors.forename: Stephane
authors.initials: S
authors.lastname: Prost
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D046528:Chimerism; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006467:Hemophilia A / Q000628:therapy; D006801:Humans; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D019089:Stem Cell Factor / Q000235:genetics*; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014916:Whole-Body Irradiation
chemical_list: D018952:Antigens, CD34; D019653:Myeloablative Agonists; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D019089:Stem Cell Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D014740:Vidarabine; C024352:fludarabine