Evaluate Anti-Fibrotic Compounds in Animal Models of NASH

It is estimated that ~25% of the world’s population is affected by non-alcoholic fatty liver disease (NAFLD). NAFLD is considered to be relatively benign, but can progress to non-alcoholic steatohepatitis (NASH) in a significant number of individuals. Currently, the only therapy to treat NAFLD/NASH are lifestyle modifications (diet and exercise), and the pharmaceutical and biotech industries are actively pursuing the discovery and development of candidate therapies to address this unmet medical need.

NASH is characterized by lobular inflammation, hepatocyte ballooning and degeneration progressing to liver fibrosis. Left unchecked, NASH can progress to full blown cirrhosis and, in some instances, hepatocellular carcinoma. However, development of NASH is not universal among those affected by NAFLD, and this is one of the factors that makes modeling NASH in animal models complex. Several animal models have been identified that faithfully replicate various aspects of the disease in a reproducible manner. NASH drug discovery scientists at Charles River have have qualified two diet-induced mouse models that are useful to assess candidate agents:

  • Feeding a choline deficient, defined amino acid (CDAA) diet to C57BL/6 mice
  • Feeding a high fructose, high fat, cholesterol (HFHC) diet to ob/ob mice

In each case, the animals develop a characteristic change in liver histopathology consistent with NASH.

 

Choline Deficient, Defined Amino Acid (CDAA) Mice

  • Study Paradigm

    Example timeline for onset of fibrosis in a CDAA-diet induced C57BL/6 mouse model of NASH. Liver biopsies performed at baseline.
    Example timeline for onset of fibrosis in a CDAA-diet induced C57BL/6 mouse model of NASH. Liver biopsies performed at baseline.

  • Validation Data

    Chart showing body weight: mice fed CDAA diet gain more weight than mice on chow diet
    Body weight: mice fed CDAA diet gain more weight than mice on chow diet.

     

    Chart showing Serum lipids are elevated in mice fed CDAA diet
    Serum biomarkers in mice fed CDAA diet compared to mice fed control diet.

     

    Chart showing histologic progression of NASH in mice fed CDAA diet. Control animals showed no disease at study termination.
    Histologic progression of NASH in mice fed CDAA diet. Control animals showed no disease at study termination.

     

    Image of H&E and Picrosirius Red staining of liver after 18wks on CDAA diet. Arrow marks area of focal inflammation.
    H&E and Picrosirius Red staining of liver after 18wks on CDAA diet. Arrow marks area of focal inflammation.

     

    Liver biopsies demonstrate varying degrees of progression in different animals within the same cohort.
    Liver biopsies demonstrate varying degrees of steatosis and fibrosis in animals prior to initiation of treatment.

     

    Animals within the same group demonstrate varying NAS scores at baseline and final biopsies.
    Biopsy scores permit evaluation of response to treatment in individual animals.

High Fructose, High Fat, Cholesterol Diet in ob/ob Mice

  • Study Paradigm

    Example timeline for onset of fibrosis in a CDAA-diet induced C57BL/6 mouse model of NASH. Liver biopsies performed at baseline.
    Example timeline for onset of fibrosis in a CDAA-diet induced C57BL/6 mouse model of NASH. Liver biopsies performed at baseline.

  • Validation Data

    Chart showing measures of body weight and blood glucose at several time points over the course of an 18-wk study
    Measures of body weight and blood glucose at several time points over the course of an 18-wk study.

     

    Chart showing biomarker profile at several timepoints over the course of an 18-wk study
    Biomarker profile at several timepoints over the course of an 18-wk study

     

    Chart showing Histology scores.Histology scores

     

    H&E and Picrosirius Red staining of liver after 18wks on HFHC diet.
    H&E and Picrosirius Red staining of liver after 18wks on HFHC diet. Left: Extensive steatosis and lobular inflammation noted. Right: Picrosirius red decoration of fibrosis.

     

    Chart showing pathology scores for lobular inflammation and fibrosis increased after 24-weeks compared to 12-week timepoint.
    Pathology scores for lobular inflammation and fibrosis increased after 24-weeks compared to 12-week timepoint.