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Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression

Gene Therapy volume 22, pages 856–865 (2015)Cite this article

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Abstract

Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 1012 viral particles kg−1 (1010 infective units kg−1) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS.

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Acknowledgements

We are grateful to Alberto Espinal and Elena Ciordia for animal care and vivarium management. We also thank Dr Laura Guembe (Morphology and Imaging Unit, CIMA, Pamplona, Italy) for help in preparing and staining the tissue sections. Victor Segura is appreciatively acknowledged for help with statistical analysis. Dr Hernández-Alcoceba, Dr González-Aparicio, Dr Prieto, Quiroga, Dr Avila and Dr Lasarte are acknowledged for helpful discussions and scientific support. This work was supported by grants from UTE project of Centro de Investigación Médica Aplicada (CIMA-University of Navarra), Fundación Mutua Madrileña and Spanish Institute of Health Carlos III (FIS) co-financed by European FEDER funds (PI09/02639 and PI12/02785).

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Authors and Affiliations

  1. Department of Pathology and Immunology, Pediatric Surgery Laboratory, Faculty of Medicine, University of Geneva, Geneva, 1211, Switzerland

    C Unzu

  2. Immunotherapy and Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    I Melero, S Hervás-Stubbs, A Sampedro, U Mancheño, A Morales-Kastresana, I Serrano-Mendioroz & A Fontanellas

  3. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    I Melero, S Hervás-Stubbs, A Benito & A Fontanellas

  4. Department of Oncology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain

    I Melero

  5. Research Center, Hospital Universitario 12 de Octubre, University Complutense of Madrid, Madrid, Spain

    R E de Salamanca

  6. Department of Radiology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain

    A Benito

  7. CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain

    A Fontanellas

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Correspondence to A Fontanellas.

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Unzu, C., Melero, I., Hervás-Stubbs, S. et al. Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression. Gene Ther 22, 856–865 (2015). https://doi.org/10.1038/gt.2015.64

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