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

Gene Therapy volume 14, pages 49–57 (2007)Cite this article

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.

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Acknowledgements

We thank Karen Pepper and Denise Petersen of the CHLA vector core facility for preparing the vectors, Ronald Faris at MultiCell Technologies Inc., Warwick, RI, USA for providing the porcine hepatocytes used for immunization and the staff of the University of California National Primate Research Center for assistance and care with the animals. This work was supported by NIH Grants 1R21 AI49922-01 and 7RO1 AI52079-02 (to MKJ) and RR00169 to the California National Primate Research Center.

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, The Saban Research Institute of Childrens Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    J Y Fischer-Lougheed, I Shulkin, N Mitsuhashi & M Kearns-Jonker

  2. California National Primate Research Center, University of California, Davis, CA, USA

    A F Tarantal & C C I Lee

  3. Division of Research Immunology/Bone Marrow Transplantation, The Saban Research Institute of Childrens Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    D B Kohn

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  1. J Y Fischer-Lougheed
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Correspondence to M Kearns-Jonker.

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Fischer-Lougheed, J., Tarantal, A., Shulkin, I. et al. Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates. Gene Ther 14, 49–57 (2007). https://doi.org/10.1038/sj.gt.3302818

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