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Combinatorial gene therapy induces regression of hepatic encephalopathy

Gene Therapy volume 18, pages 88–94 (2011)Cite this article

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Abstract

Capillarization of the sinusoid impedes the clearance of neurotoxic substances in liver fibrosis. These events may result in hepatic encephalopathy. Neurological and hepatic features of rats after bile duct ligation (BDL) supplemented with Manganese (BDL+Mn2+) were examined. The 4-week-old BDL rats had elevated levels of ammonia and were concomitantly fed with 1 mg ml−1 of MnCl2 in drinking water (BDL/Mn+2). Five out of fifteen rats were killed and the serum, liver and brain tissue (striatum and substantia nigra) were recovered. Of the remaining BDL/Mn+2-cirrhotic animals (n=10), five were injected with a combination of Adenovirus-human plasminogen activator (Ad-huPA) and Adenovirus-matrix metalloproteinase-8 (Ad-MMP-8) (3 × 1011+1.5 × 1011 vector particles per kg), and five with 4.5 × 1011 vector particles per kg of Adenovirus-β-galactosidase (Ad-β-Gal). This treatment was carried on for 10 days. The BDL/Mn+2 rats displayed tremor, rigidity and gait abnormalities, which improved notably with combinatorial gene therapy, as well as motor coordination. Liver fibrosis was evidently less after treatment with Ad-huPA+Ad-MMP-8 (25%). In the brain (striatum), Ad-huPA+Ad-MMP-8 treatment rendered higher concentrations of dopamine compared with Ad-β-Gal-treated encephalopathic rats (210 and 162 ng g−1 of tissue, respectively). The BDL/Mn+2 animals and controls treated with Ad-β-Gal showed abnormal morphology in astrocytes (gliosis) in striatum and substantia nigra, in which expressions of green fibrillar acidic protein and tyrosine hydroxylase were altered. These abnormalities decreased with Ad-huPA+Ad-MMP-8 treatment. Importantly, the latter animals showed an increment in sprouting of nervous fibers in substantia nigra. Combinatorial gene therapy improves neuroanatomical and neurochemical characteristics similar to human hepatic encephalopathy.

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Acknowledgements

This study was financially supported by COECyT-Jal (code number 08-2004) and CONACyT 25474 awarded to JAB.

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Authors and Affiliations

  1. Institute for Molecular Biology and Gene Therapy, CUCS, University of Guadalajara, Jalisco, México

    F J Gálvez-Gastélum, J J Garcia-Bañuelos, A Segura-Flores, A Salazar-Montes, A S Sandoval-Rodriguez, M Bueno-Topete, S Lucano-Landeros & J Armendáriz-Borunda

  2. Laboratory of Molecular and Cell Neurobiology, CIBO, IMSS and CUCBA, University of Guadalajara, México

    C Beas-Zárate & V Chaparro-Huerta

  3. Pharmacology Department, Research and Pharmaceutical Development Laboratory, CUCEI, University of Guadalajara, México

    H González

  4. OPD Civil Hospital, Guadalajara, México

    D Medina-Preciado, I Gonzalez-Garcia & J Armendáriz-Borunda

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  1. F J Gálvez-Gastélum
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  2. J J Garcia-Bañuelos
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  7. A Salazar-Montes
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  9. M Bueno-Topete
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  10. S Lucano-Landeros
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Correspondence to J Armendáriz-Borunda.

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Gálvez-Gastélum, F., Garcia-Bañuelos, J., Beas-Zárate, C. et al. Combinatorial gene therapy induces regression of hepatic encephalopathy. Gene Ther 18, 88–94 (2011). https://doi.org/10.1038/gt.2010.107

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