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Simian immunodeficiency virus lentivector corrects human X-linked chronic granulomatous disease in the NOD/SCID mouse xenograft

Gene Therapy volume 14, pages 1513–1524 (2007)Cite this article

Abstract

X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the phagocyte nicotinamide dinucleotide phosphate oxidase catalytic subunit gp91phox. Gene therapy targeting hematopoietic stem cells (HSCs) can correct CGD, but permanent correction remains a challenge. Lentiviral vectors have become attractive tools for gene transfer, and they may have the potential to transduce very primitive HSCs. We used a self-inactivating RD114/TR-pseudotyped simian immunodeficiency virus (SIVmac)-based vector encoding human gp91phox for ex vivo transduction of peripheral blood-mobilized stem cells (PBSCs) from patients with X-CGD. In PBSCs from two patients, ex vivo transduction efficiencies of 40.5 and 46% were achieved, and correction of oxidase activity was observed in myeloid cells differentiating in culture. When transduced PBSCs from these patients were transplanted into nonobese diabetic/severe combined immunodeficient mice and compared to normal control, 10.5 and 7.3% of the human myeloid cells in bone marrow developing at 6 weeks from the human xenografts expressed the gp91phox transgene. Sustained functional correction of oxidase activity was documented in myeloid cells differentiated from engrafted transduced PBSCs. Transgene marking was polyclonal as assessed by vector integration site analysis. These data suggest that RD114/TR SIVmac-based vectors might be suitable for gene therapy of CGD and other hereditary hematologic diseases.

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Acknowledgements

We are grateful to the laboratory of Arthur W Nienhuis (Experimental Hematology Division, Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN, USA) for providing the parental SIVmac vector system. We thank Larry Lantz (Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA) for purification of the TM-β1 antibody. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

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Authors and Affiliations

  1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    N Naumann, S S De Ravin, U Choi, M Moayeri, N Whiting-Theobald, G F Linton & H L Malech

  2. Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN, USA

    Y Ikeda

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  1. N Naumann
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Correspondence to H L Malech.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt).

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Naumann, N., De Ravin, S., Choi, U. et al. Simian immunodeficiency virus lentivector corrects human X-linked chronic granulomatous disease in the NOD/SCID mouse xenograft. Gene Ther 14, 1513–1524 (2007). https://doi.org/10.1038/sj.gt.3303010

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