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Adenovirus Biodistribution is Modified in Sensitive Animals Compared to Naïve Animals

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Abstract

Pre-existing immune response against adenovirus could diminish transgene expression efficiency when Ad is employed in humans as gene therapy vector. We previously used Ad-hΔuPA (Recombinant adenovirus expressing human urokinase-type plasminogen activator) as antifibrotic gene therapy in cirrhosis models and demonstrated its effectiveness. As a further clinical approach, transient Cyclosporine A (CsA) immunosuppression was induced in cirrhotic animals to determine whether Ad-hΔuPA administration retained efficacy. Adenovirus sensitization was achieved by systemic administration of non-therapeutic Ad-βGal (Recombinant adenovirus expressing beta-galactosidase) after 4 weeks of intraperitoneal carbon tetrachloride (CCl4) regimen. Cirrhosis induction continued up to 8 weeks. At the end of CCl4 intoxication, immunosuppression was achieved with three CsA doses (40 mg/kg) as follows: 24 h before administration of Ad-hΔuPA, at the moment of Ad-hΔuPA injection and finally, 24 h after Ad-hΔuPA inoculation. At 2 and 72 h after Ad-hΔuPA injection, animals were sacrificed. Liver, spleen, lung, kidney, heart, brain, and testis were analyzed for Ad-biodistribution and transgene expression. In naïve animals, Ad-hΔuPA genomes prevailed in liver and spleen, while Ad-sensitized rats showed Ad genomes also in their kidney and heart. Cirrhosis and Ad preimmunization status notably diminished transgene liver expression compared to healthy livers. CsA immunosuppression in cirrhotic animals has no effect on Ad-hΔuPA biodistribution, but increments survival.

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Acknowledgements

Authors want to thank Conacyt for Grant Number 103772 awarded to Ana Sandoval Rodriguez and Conacyt Grant Number 259096 awarded to Juan Armendariz-Borunda

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Authors and Affiliations

  1. Department of Molecular Biology and Genomics, Institute for Molecular Biology and Gene Therapy, University of Guadalajara, Sierra Mojada 950, Colonia Independencia, Edificio Q. Tercer Piso, CP 44340, Guadalajara, Jalisco, Mexico

    Ana Sandoval-Rodríguez, Jesús García-Bañuelos, Adriana Salazar-Montes & Juan Armendariz-Borunda

  2. Department of Health Sciences, University of Guadalajara, Av. Periférico Oriente 555, Ejido San José Tateposco, CP 48525, Tonalá, Jalisco, Mexico

    Mayra Mena-Enriquez

  3. Tecnologico de Monterrey, Campus Guadalajara, Guadalajara, Jalisco, Mexico

    Arturo Santos-García & Juan Armendariz-Borunda

  4. Department of Physiology, Research Center for Immunology and Dermatology, University of Guadalajara, Av Federalismo Norte 3102, Atemajac del Valle, 45190, Zapopan, Jalisco, Mexico

    Mary Fafutis-Morris

  5. IIRSME, CUCS, University of Guadalajara, Guadalajara, Mexico

    Monica Vázquez-Del Mercado

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  1. Ana Sandoval-Rodríguez
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Correspondence to Juan Armendariz-Borunda.

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Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice where the studies were conducted. The protocol was approved by the Research and Ethical Committee of the CUCS, Universidad de Guadalajara (Approval Number C.I. 67-2012) which reviewed and approved the mortality aspects of the protocol.

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Sandoval-Rodríguez, A., Mena-Enriquez, M., García-Bañuelos, J. et al. Adenovirus Biodistribution is Modified in Sensitive Animals Compared to Naïve Animals. Mol Biotechnol 62, 260–272 (2020). https://doi.org/10.1007/s12033-020-00247-x

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  • DOI: https://doi.org/10.1007/s12033-020-00247-x

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