Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates

J. Y. Fischer-Lougheed, Alice F Tarantal, I. Shulkin, N. Mitsuhashi, D. B. Kohn, Charles C Lee, M. Kearns-Jonker

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Xenoantibodies to the galα1,3 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 α1,3-galactosyltransferase (α1,3GT)-/- mice using lentiviral vectors expressing porcine α1,3GT, 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, α1,3GT-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 α1,3GT 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.

Original languageEnglish (US)
Pages (from-to)49-57
Number of pages9
JournalGene Therapy
Volume14
Issue number1
DOIs
StatePublished - Jan 2007

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Heterophile Antibodies
Galactosyltransferases
Chimerism
Genetic Therapy
Primates
Swine
Simian Immunodeficiency Virus
Macaca mulatta
HIV-1
Immunization
Bone Marrow
Heterologous Transplantation
Haplorhini
Immunoglobulin M
Epitopes
Anti-Idiotypic Antibodies
Hepatocytes
Transplantation
Carbohydrates
Tissue Donors

Keywords

  • Chimerism
  • Lentiviral vector
  • Primate
  • Rhesus monkeys
  • Xenotransplanation

ASJC Scopus subject areas

  • Genetics

Cite this

Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates. / Fischer-Lougheed, J. Y.; Tarantal, Alice F; Shulkin, I.; Mitsuhashi, N.; Kohn, D. B.; Lee, Charles C; Kearns-Jonker, M.

In: Gene Therapy, Vol. 14, No. 1, 01.2007, p. 49-57.

Research output: Contribution to journalArticle

Fischer-Lougheed, JY, Tarantal, AF, Shulkin, I, Mitsuhashi, N, Kohn, DB, Lee, CC & Kearns-Jonker, M 2007, 'Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates', Gene Therapy, vol. 14, no. 1, pp. 49-57. https://doi.org/10.1038/sj.gt.3302818
Fischer-Lougheed, J. Y. ; Tarantal, Alice F ; Shulkin, I. ; Mitsuhashi, N. ; Kohn, D. B. ; Lee, Charles C ; Kearns-Jonker, M. / Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates. In: Gene Therapy. 2007 ; Vol. 14, No. 1. pp. 49-57.
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