Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer

Studies in infant ADA-Deficient mice and rhesus monkeys

Denise Carbonaro Sarracino, Alice F. Tarantal, C. Chang I Lee, Michele Martinez, Xiangyang Jin, Xiaoyan Wang, Cinnamon L. Hardee, Sabine Geiger, Christoph Kahl, Donald B. Kohn

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    Systemic delivery of a lentiviral vector carrying a therapeutic gene represents a new treatment for monogenic disease. Previously, we have shown that transfer of the adenosine deaminase (ADA) cDNA in vivo rescues the lethal phenotype and reconstitutes immune function in ADA-deficient mice. In order to translate this approach to ADA-deficient severe combined immune deficiency patients, neonatal ADA-deficient mice and newborn rhesus monkeys were treated with species-matched and mismatched vectors and pseudotypes. We compared gene delivery by the HIV-1-based vector to murine γ-retroviral vectors pseudotyped with vesicular stomatitis virus-glycoprotein or murine retroviral envelopes in ADA-deficient mice. The vesicular stomatitis virus-glycoprotein pseudotyped lentiviral vectors had the highest titer and resulted in the highest vector copy number in multiple tissues, particularly liver and lung. In monkeys, HIV-1 or simian immunodeficiency virus vectors resulted in similar biodistribution in most tissues including bone marrow, spleen, liver, and lung. Simian immunodeficiency virus pseudotyped with the gibbon ape leukemia virus envelope produced 10- to 30-fold lower titers than the vesicular stomatitis virus-glycoprotein pseudotype, but had a similar tissue biodistribution and similar copy number in blood cells. The relative copy numbers achieved in mice and monkeys were similar when adjusted to the administered dose per kg. These results suggest that this approach can be scaled-up to clinical levels for treatment of ADA-deficient severe combined immune deficiency subjects with suboptimal hematopoietic stem cell transplantation options.

    Original languageEnglish (US)
    Pages (from-to)1803-1816
    Number of pages14
    JournalMolecular Therapy
    Volume22
    Issue number10
    DOIs
    StatePublished - Jan 1 2014

    Fingerprint

    Vesicular Stomatitis
    Adenosine Deaminase
    Macaca mulatta
    Severe Combined Immunodeficiency
    Simian Immunodeficiency Virus
    Glycoproteins
    Viruses
    Haplorhini
    HIV-1
    Gibbon ape leukemia virus
    Genes
    Lung
    Blood Cell Count
    Liver
    Hematopoietic Stem Cell Transplantation
    Therapeutics
    Spleen
    Complementary DNA
    Bone Marrow
    Phenotype

    ASJC Scopus subject areas

    • Molecular Biology
    • Molecular Medicine
    • Genetics
    • Drug Discovery
    • Pharmacology

    Cite this

    Sarracino, D. C., Tarantal, A. F., Lee, C. C. I., Martinez, M., Jin, X., Wang, X., ... Kohn, D. B. (2014). Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: Studies in infant ADA-Deficient mice and rhesus monkeys. Molecular Therapy, 22(10), 1803-1816. https://doi.org/10.1038/mt.2014.88

    Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer : Studies in infant ADA-Deficient mice and rhesus monkeys. / Sarracino, Denise Carbonaro; Tarantal, Alice F.; Lee, C. Chang I; Martinez, Michele; Jin, Xiangyang; Wang, Xiaoyan; Hardee, Cinnamon L.; Geiger, Sabine; Kahl, Christoph; Kohn, Donald B.

    In: Molecular Therapy, Vol. 22, No. 10, 01.01.2014, p. 1803-1816.

    Research output: Contribution to journalArticle

    Sarracino, DC, Tarantal, AF, Lee, CCI, Martinez, M, Jin, X, Wang, X, Hardee, CL, Geiger, S, Kahl, C & Kohn, DB 2014, 'Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: Studies in infant ADA-Deficient mice and rhesus monkeys', Molecular Therapy, vol. 22, no. 10, pp. 1803-1816. https://doi.org/10.1038/mt.2014.88
    Sarracino, Denise Carbonaro ; Tarantal, Alice F. ; Lee, C. Chang I ; Martinez, Michele ; Jin, Xiangyang ; Wang, Xiaoyan ; Hardee, Cinnamon L. ; Geiger, Sabine ; Kahl, Christoph ; Kohn, Donald B. / Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer : Studies in infant ADA-Deficient mice and rhesus monkeys. In: Molecular Therapy. 2014 ; Vol. 22, No. 10. pp. 1803-1816.
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