title: Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates.
abstract: Xenoantibodies to the gal alpha1,3 gal (gal) epitope impede the use of pig tissues for xenotransplantation, a procedure that may help overcome the shortage of human organ donors. Stable gal chimerism and tolerance to gal(+) hearts could be achieved in alpha1,3-galactosyltransferase (alpha1,3GT)(-/-) mice using lentiviral vectors expressing porcine alpha1,3GT, the enzyme that synthesizes the gal carbohydrate. In this study, we evaluated whether chimerism sufficient to inhibit anti-gal xenoantibody responses can be achieved using lentivectors in non-human primates. Rhesus macaques were transplanted with autologous, alpha1,3GT-transduced bone marrow (BM) following sublethal irradation. Simian immunodeficiency virus (SIV)- and human immunodeficiency virus (HIV)-1-derived lentiviral constructs were compared. Chimerism was observed in several hematopoietic lineages in all monkeys. Engraftment in animals receiving SIV-based alpha1,3GT constructs was similar to that achieved using the HIV-1-derived lentivector for the first 2 months post-transplantation, but increased thereafter to reach higher levels by 5 months. Upon immunization with porcine hepatocytes, the production of anti-gal immunoglobulin M xenoantibody was substantially reduced in the gal(+) BM recipients compared to controls. This study is the first to report the application of gene therapy to achieve low-level, long-term gal chimerism sufficient to inhibit production of anti-gal antibodies after immunization with porcine cells in rhesus macaques.
authors.affiliation: Department of Cardiothoracic Surgery, The Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Fischer-Lougheed
authors.forename: A F
authors.initials: AF
authors.lastname: Tarantal
authors.forename: I
authors.initials: I
authors.lastname: Shulkin
authors.forename: N
authors.initials: N
authors.lastname: Mitsuhashi
authors.forename: D B
authors.initials: DB
authors.lastname: Kohn
authors.forename: C C I
authors.initials: CC
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Kearns-Jonker
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000276:immunology*; D000917:Antibody Formation; D016026:Bone Marrow Transplantation / Q000379:methods; D002678:Chimera; D000939:Epitopes / Q000276:immunology; D005700:Galactosyltransferases / Q000235:genetics* / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006084:Graft Rejection / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics; D007075:Immunoglobulin M / Q000032:analysis; D008252:Macaca fascicularis; D023421:Models, Animal; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D013552:Swine; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D000939:Epitopes; D007075:Immunoglobulin M; D005700:Galactosyltransferases; C487611:alpha 1,3 galactosyltransferase, mouse