Advancing the Alb-uPA/SCID/Bg Chimeric Mouse

Abstract

The feasibility of the Alb-uPA/SCID/Bg chimeric mouse as a model for Hepatitis C Virus (HCV) infection was assessed experimentally by (1) the infection and treatment with another hepatotropic virus, Hepatitis B Virus (HBV) and (2) the infection of the model with HCV and the subsequent treatment of that infection with a pro-apoptotic factor (BID) targeted to infected hepatocytes. In the former, the infected mouse responded favorably, and in the manner of human patients, to a standard imunoglobulin therapy. In the latter, HCV-infected hepatocytes were successfully targeted for cell death, with repeated doses of Adenovirus-delivered BID being the most effective at inhibiting virus spread. Efficacy and toxic side-effects of BID treatment could be reconciled by modulating the timing between doses, the most effective tested being three doses of BID at 7-day intervals. Analyses of chimeric model production were undertaken to improve the quality of human hepatocyte engraftment (typically only 25-35% of mice receiving grafts are currently used experimentally). Minor variations in success rates were experienced with respect to donor age or health status, or the age of recipient mice within an operational window of 5 to 13 days from birth. The greatest obstacle to useful engraftment (aside from technical challenges) was deemed to be the genetic/cellular integrity of the recipient mouse. This conclusion was based on variable engraftment success with ‘healthy’ donor cell preparations and a consideration of variability in immune deficiency arising in mice within a SCID/Bg mouse colony.