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Published on: January 7, 2019
Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application
Norman M Kneteman1, Amy J Weiner, John O'Connell
1Department of Surgery, University of Alberta, Edmonton, Canada. nkneteman@cha.ab.ca
Abstract:
Compounds with in vitro anti-hepatitis C virus (HCV) activity are often advanced directly into clinical trials with limited or no in vivo efficacy data. This limits prediction of clinical efficacy of compounds in the HCV drug pipeline, and may expose human subjects to unnecessary treatment effects. The scid-Alb-uPA mouse supports proliferation of transplanted human hepatocytes and subsequent HCV infection. Cohorts of genotype 1a HCV-infected mice were treated with interferon alpha-2b(IFN-alpha), BILN-2061 (anti-NS3 protease), or HCV371 (anti-NS5B polymerase). Mice treated with 1350 IU/g/day IFN-alpha intramuscularly for 10 to 28 days demonstrated reduced viral titers compared with controls in all five experiments (P < .05, t test); viral titers rebounded after treatment withdrawal. A more pronounced antiviral effect with IFN-alpha was seen in genotype 3a-infected mice. Pilot studies with BILN2061 confirmed exposure to 10X replicon EC50 at trough and reduced viral titer over 2 log at 4 days. In a second 7-day study, mean HCV RNA titers dropped 1.1 log in BILN2061-treated animals, 0.6 log in IFN-treated mice, and rose 0.2 log in controls (P = .013, ANOVA). Pre-existing mutants with partial resistance to BILN2061 were identified by sequencing both the human inoculum and sera from treated mice. The polymerase inhibitor HCV371 yielded a decline in HCV titers of 0.3 log relative to vehicle-treated controls (P = NS). Performance of all three antiviral regimens in the chimeric mouse model paralleled responses in humans. In conclusion, this system may help selection of lead compounds for advancement into human trials with an increased likelihood of clinical success while broadening the tools available for study of the biology of HCV infection.
Insights
This study introduces a chimeric mouse model for testing hepatitis C virus (HCV) drugs. The model effectively predicted human responses to antiviral treatments, aiding in selecting effective HCV compounds for clinical trials.
Area of Science:
- Hepatology and Virology
- Drug Discovery and Development
- Preclinical Animal Models
Background:
- Many hepatitis C virus (HCV) drug candidates lack in vivo efficacy data, hindering clinical trial success prediction.
- Limited preclinical data can lead to exposing human subjects to ineffective treatments and potential side effects.
- A need exists for reliable animal models to assess HCV drug efficacy before human trials.
Purpose of the Study:
- To evaluate the utility of a scid-Alb-uPA chimeric mouse model for assessing in vivo efficacy of anti-HCV compounds.
- To compare the antiviral effects of interferon alpha-2b (IFN-alpha), BILN-2061 (protease inhibitor), and HCV371 (polymerase inhibitor) in HCV-infected chimeric mice.
- To determine if the chimeric mouse model can predict clinical responses to HCV antivirals.
Main Methods:
- Human hepatocytes were transplanted into scid-Alb-uPA mice, which were subsequently infected with genotype 1a HCV.
- Mice received intramuscular interferon alpha-2b (IFN-alpha), BILN-2061, or HCV371 for varying durations.
- Viral titers were measured, and drug resistance mutations were analyzed by sequencing.
Main Results:
- IFN-alpha treatment reduced HCV titers in mice, with rebound observed post-treatment; a stronger effect was noted in genotype 3a-infected mice.
- BILN-2061 demonstrated significant antiviral activity, reducing viral titers by over 2 logs in pilot studies and 1.1 logs in a subsequent 7-day study.
- HCV371 showed a minimal effect (0.3 log decline), and resistance mutations to BILN-2061 were detected.
- The model's performance for all tested antivirals paralleled known human responses.
Conclusions:
- The scid-Alb-uPA chimeric mouse model effectively supports HCV infection and treatment studies.
- This model demonstrates predictive value for clinical efficacy, mirroring human responses to IFN-alpha and direct-acting antivirals.
- The system offers a valuable tool for selecting promising HCV drug candidates and studying HCV biology, potentially improving clinical trial success rates.
