Figure 5.

Effects on mitochondrial function and structure in a rat carcinogenicity study with two STC GalNAc–siRNAs. Male and female Sprague Dawley rats were dosed subcutaneously once weekly with revusiran at 10, 30 or 100 mg/kg or siTTR-3 (rodent TTR) at 30 mg/kg for the duration of the study. (A) Plasma lactate at the terminal necropsy (day 675 for males and day 612 for females). Each data point represents an individual animal; males (N = 10) and females (N = 10) were pooled. There were no statistically significant differences between groups (P > 0.05). Levene’s test was done to test for equality of variances between groups. Levene’s test was not significant (P > 0.05) and therefore ANOVA was conducted on the untransformed data. The group effect of the ANOVA was significant (P ≤ 0.05) and therefore Dunnett’s t-test was used for pairwise comparisons between each revusiran- and siTTR-3-treated and control group. Group comparisons (revusiran and siTTR-3 groups versus saline group) were evaluated at the 5.0%, two-tailed probability level. (B) Left panel: portal hepatocytes from one control female; right panel: portal hepatocytes from one female administered 100 mg/kg revusiran. Note the increased lipid vacuoles and numerous elongated and/or ring-shaped or cup-shaped mitochondria in the hepatocytes of the treated animal compared with control. Both images are of 2650× magnification. (C) Left panel: mitochondria from centrilobular hepatocyte of one control female; right panel: mitochondria from centrilobular hepatocyte of one male administered 100 mg/kg revusiran. The mitochondrial cristae are similar in both animals. Both images are of 53 000× magnification.