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 Scopus citations

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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Keywords

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

ASJC Scopus subject areas

  • Genetics

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