Análisis del efecto terapéutico y los mecanismos moleculares inducidos por vectores virales que expresan el factor de crecimiento similar a la insulina de tipo i (igf-i) en el tratamiento de la cirrosis hepática

Abstract

Previous studies have demostrated that the administration of recombinant IGF-I protein is effective in the treatment of liver cirrhosis. However, the short half life of IGF-I in serum and the high price of recombinant IGF-I protein production, make this treatment exceedingly costly. Therefore, we have analyzed the therapeutic effect in liver cirrhosis of IGF-I gene transfer using viral vectors. We have used recombinant viral vectors expressing rat IGF-I based on simian virus 40 (rSVIGF-I) or adeno-associated vectors (rAAVIGF-I). We have inyected these vectors before or after cirrhosis induction in rats. Cirrhosis has been developed by intragastric administration of CCl4. Both pretreatment and treatment of liver cirrhosis with rSVIGF-I or rAAVIGF-I induced a curative process that resulted in improved liver functionality and decreased liver fibrosis. This therapeutic effect seems mediated by the IGF-I-dependent induction of cytoprotective and antifibrogenic molecules and the inhibition of profibrogenic factors. Thus, IGF-I expression reprograms the liver from a ¿scar formation¿ program, which leads to cirrhosis, to a ¿tissue repair¿ circuit that favours cirrhosis regression. Surprisingly, therapy was less efficient when rSVIGF-I or high doses of AAVIGF-I were used. None of the vectors showed toxic effects in cirrhotic or healthy animals. The therapeutic effects observed with low doses of AAV vectors expressing IGF-I allows us to suggest that these vectors could base a useful therapy for patients that deteriorate in the waiting list for liver transplantation or for those patients non-suitable for liver transplant.