Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application

Norman M. Kneteman, Amy J. Weiner, John O'Connell, Marc Collett, Tiejun Gao, Lea Aukerman, Rosemary Kovelsky, Zhi Jie Ni, Ahmad Hashash, Janine Kline, Belinda Hsi, Daniel Schiller, Donna Douglas, D. Lorne J. Tyrrell, David F. Mercer

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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 α-2b (IFN-α), BILN-2061 (anti-NS3 protease), or HCV371 (anti-NSSB polymerase). Mice treated with 1350IU/g/day IFN-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)1346-1353
Number of pages8
JournalHepatology
Volume43
Issue number6
DOIs
StatePublished - Jun 1 2006

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Hepacivirus
Interferons
Virus Diseases
Viral Load
Therapeutics
Antiviral Agents
Genotype
Replicon
Hepatocytes
Analysis of Variance
Peptide Hydrolases
Clinical Trials
RNA
BILN 2061
Serum
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hepatology

Cite this

Kneteman, N. M., Weiner, A. J., O'Connell, J., Collett, M., Gao, T., Aukerman, L., ... Mercer, D. F. (2006). Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. Hepatology, 43(6), 1346-1353. https://doi.org/10.1002/hep.21209

Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. / Kneteman, Norman M.; Weiner, Amy J.; O'Connell, John; Collett, Marc; Gao, Tiejun; Aukerman, Lea; Kovelsky, Rosemary; Ni, Zhi Jie; Hashash, Ahmad; Kline, Janine; Hsi, Belinda; Schiller, Daniel; Douglas, Donna; Tyrrell, D. Lorne J.; Mercer, David F.

In: Hepatology, Vol. 43, No. 6, 01.06.2006, p. 1346-1353.

Research output: Contribution to journalArticle

Kneteman, NM, Weiner, AJ, O'Connell, J, Collett, M, Gao, T, Aukerman, L, Kovelsky, R, Ni, ZJ, Hashash, A, Kline, J, Hsi, B, Schiller, D, Douglas, D, Tyrrell, DLJ & Mercer, DF 2006, 'Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application', Hepatology, vol. 43, no. 6, pp. 1346-1353. https://doi.org/10.1002/hep.21209
Kneteman NM, Weiner AJ, O'Connell J, Collett M, Gao T, Aukerman L et al. Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. Hepatology. 2006 Jun 1;43(6):1346-1353. https://doi.org/10.1002/hep.21209
Kneteman, Norman M. ; Weiner, Amy J. ; O'Connell, John ; Collett, Marc ; Gao, Tiejun ; Aukerman, Lea ; Kovelsky, Rosemary ; Ni, Zhi Jie ; Hashash, Ahmad ; Kline, Janine ; Hsi, Belinda ; Schiller, Daniel ; Douglas, Donna ; Tyrrell, D. Lorne J. ; Mercer, David F. / Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. In: Hepatology. 2006 ; Vol. 43, No. 6. pp. 1346-1353.
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