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418
CRV431, a Cyclophilin Inhibitor, Reduces
Fibrosis and Tumor Burden in Mice with
Hepatocellular Carcinoma
Joseph Kuo1, Michael Bobardt1, Udayan Chatterji1, Daniel
Trepanier2, Daren Ure2, Philippe Gallay1 and Robert Foster2,
(1)Immunology & Microbiology, The Scripps Research
Institute, (2)Contravir Pharmaceuticals Inc.
Background: An important objective in the treatment of
hepatitis B is the reduction of liver disease, including fibrosis,
cirrhosis, and hepatocellular carcinoma (HCC), arising from
chronic hepatitis B virus (HBV) infection. Previous studies
have shown that cyclophilin isomerases, in addition to their
beneficial role in protein folding, also paradoxically contribute
to a variety of injury and disease processes. The aim of
this study was to examine whether the cyclophilin inhibitor,
CRV431, in addition to its antiviral activities, also reduces
characteristics of liver disease in a mouse model. The nonalcoholic
steatohepatitis (NASH) mouse model was used to
assess liver-protective effects of CRV431, since this model
exhibits many pathogenic outcomes in similarity to chronic
HBV infection, including inflammation, fibrosis, and HCC.
Methods: Mice were administered streptozotocin, followed
by a high-fat diet for either 11 or 27 weeks, for assessment of
fibrosis and HCC development, respectively. CRV431 50 mg/
kg or vehicle control were administered orally each day for the
final 6 or 10 weeks of the two studies, respectively. In the HCC
study, CRV431 dosing was initiated once the presence of
nodules was confirmed. Livers were examined morphologically
and histologically for assessment of steatosis, inflammation,
fibrosis, and HCC tumor burden. HCC was scored according
to a developed system incorporating number and size of
nodules. Systemic cytokine levels in serum were detected by
multiplex assays. Results: CRV431 showed beneficial effects
by reducing liver fibrosis and HCC development. Liver fibrosis,
measured morphometrically following Sirius Red staining,
was reduced by 46% with CRV431 administration compared
with vehicle control (p=0.03). CRV431 reduced the number
of tumor nodules by 44% and reduced total tumor burden
by 52% compared to vehicle (p=0.02). Significantly, 25% of
CRV431-treated mice had no liver tumors at the end of the
study, whereas all vehicle-treated mice had at least 5 tumors
per liver. The reduction in tumor burden was associated with
reductions in body and liver weights. No effects of CRV431
were observed on steatosis, inflammation, systemic cytokine
levels, or blood glucose levels. Conclusion: CRV431
represents a well-tolerated and potent candidate treatment for
chronic HBV. The present study demonstrates that CRV431
may potentially benefit patients not only through its anti-HBV
activities but also by reducing development of fibrosis and
HCC.
Disclosures:
Robert Foster – ContraVir Pharmaceuticals Inc.: Employment
The following people have nothing to disclose: Joseph Kuo, Udayan Chatterji
Disclosure information not available at the time of publication: Michael Bobardt,
Daniel Trepanier, Daren Ure, Philippe Gallay |
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发表于 2018-10-18 13:56
