Therapeutic effect of a novel truncated isoform of the human TGF-β type II receptor Fc-tag protein in a liver fibrosis rat model

LA COLLA A; CÁMARA CA; BERTOLIO MS; RODRÍGUEZ TM; ECHARTE SM; DEWEY RA; CHISARI AN

Congreso; Reunión Anual de Sociedad Argentina de Fisiología 2021; 2021

SAFIS

Liver fibrosis is a hallmark feature of liver diseases. Current therapeutic options for these patients are limited. It is well established that transforming growth factor beta (TGF-β) promotes liver fibrosis. As a result, the development of agents with a high potential for achieving a specific and long-lasting block of TGF-β action, is clinically relevant. We have recently described the presence in human cells of a new splicing variant of TGF-β type II receptor that renders a truncated mature protein of 57 amino acids known as TβRII-SE. Previously, we showed that lentiviral-mediated overexpression of this truncated endogen isoform of the human TGF-β type II receptor Fc-tagged protein (Lv.TβRII-SE/Fc) had a strong prophylactic effect in preventing liver injury, inflammation and fibrosis. In this line, the aim of this work was to study, in a carbon tetrachloride (CCl4)-induced liver fibrosis rat model, the therapeutic effect of Lv.TβRII-SE/Fc. Experimental groups were designed as follows: The control group received CCl4 vehicle; the CCl4 group received CCl4 for 10 weeks; and the Lv.TβRII-SE/Fc + CCl4 group received CCl4 for 10 weeks and Lv.TβRII-SE/Fc at week 4 (n=4-5). Two-way ANOVA was employed; data was shown as mean + SD. Compared to the CCl4 group, Lv.TβRII-SE/Fc treated animals showed decreased liver to body weight (BW) ratio, spleen to BW ratio, and alleviation of the irregular shape and shrinkage of the liver. Administration of Lv.TβRII-SE/Fc also significantly diminished CCl4-induced liver enzyme elevation (Aspartate transaminase and Alanine transaminase). Histological analysis of liver sections revealed that liver architecture, liver injury, inflammation and fibrosis were attenuated in Lv.TβRII-SE/Fc + CCl4 animals. These results suggest that lentiviral delivery of TβRII-SE/Fc regulates liver injury and fibrosis to exert its therapeutic effect against CCl4-induced liver fibrosis in rats. All in all, TβRII-SE/Fc represents a good candidate for further development of a novel antifibrotic liver treatment.