Gene therapy wuth urokinase-type plasminogen activator regenerates liver tissue La terapia génica con el activador de plasminógeno tipo urocinasa media la regeneración hepática Academic Article in Scopus uri icon

abstract

  • © 2021 Academia Nacional de Medicina de México, A.C.Background and objectives: Gene therapy using urokinase-type plasminogen activator (uPA) has been shown to induce extracellular matrix degradation, hepatocyte proliferation and liver tissue function restoration in liver cirrhosis models. Physiologically, uPA activates plasminogen conversion to plasmin, which leads, depending on the organ, to thrombolysis or extracellular matrix degradation. The purpose of this study was to compare the regenerative effect of gene therapy with adenoviruses encoding wild-type uPA (huPA), as well as its truncated isoform (¿huPA), in healthy and cirrhotic animals. In addition, possible adverse effects on coagulation were assessed. Methods: 6 x 1011 vp/kg of Ad-huPA or Ad-¿huPA were administered via the iliac vein to healthy male Wistar rats or to male Wistar rats with cirrhosis induced by chronic poisoning with carbon tetrachloride (CCl4). The animals were sacrificed at day 2, 4 or 6 post-treatment. Liver fibrosis, proliferating cell nuclear antigen expression, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels and coagulation markers were evaluated. Results: On day 6 post-treatment, a fibrosis reversal of 48.7-41.5 % was achieved. AST and ALT levels did not change in cirrhotic animals treated with ¿huPA, but showed an elevation in healthy animals. Cell proliferation increased in healthy and cirrhotic animals with both transgene isoforms. No coagulation adverse effects were observed in the ¿huPA group, and by day 6, they had disappeared in the huPA group. Conclusions: Gene therapy with Ad-huPA and Ad-¿huPA favors cell proliferation in cirrhotic animals, without important side effects.

publication date

  • September 1, 2021