Abstract 394
IN VIVO ORAL DOSING OF THE TLR7 AGONIST GS-9620 INDUCES AN ANTI-VIRAL GENE EXPRESSION SIGNATURE IN MURINE LIVER CONCURRENT WITH UNDETECTABLE SERUM LEVELS OF IFN-α Move back Print add this item to your Itinerary
S. Pflanz*, A. Fosdick, T. Cihlar, M. Subramanian
Gilead Sciences, Foster City, CA, USA. *stefan.***@****
Background and aims: The selective oral TLR7 agonist GS-9620 is being developed for the treatment of chronic viral hepatitis by safely inducing long-term immune control after finite therapy. The mechanism of GS-9620-mediated anti-viral effects involves secretion of type I interferons, e.g. IFN-α. The goal GS-9620 therapy is to induce a local hepatic anti-viral response in the absence of systemic IFN-α to avoid interferon-mediated adverse effects. In this in vivo study we investigated whether a low oral dose of GS-9620 can induce a hepatic anti-viral gene expression signature in the absence of detectable serum levels of IFN-α.
Methods: Nine weeks old male CD-1 mice received vehicle or a single dose of 0.3 mg/kg GS-9620 via oral gavage and were sacrificed at 2, 4, 8, 12, and 24 h post-dose (n=5 per time point). Serum levels of IFN-α were assessed together with the liver expression of anti-viral genes MX1, OAS1, and ISG15.
Results: GS-9620 induced transient expression of hepatic OAS1, MX1, and ISG15 in all treated animals. Undetectable serum IFN-α (< 8 pg/ml) was observed in 2/5 to 5/5 animals at each terminal time point. At 2 to 12 h post-dose, all animals with undetectable serum IFN-α had concurrent two-fold or higher elevation of the hepatic expression of OAS1, MX1, or ISG15 (Figure 1). At 24 h, the hepatic anti-viral gene expression was comparable to vehicle-treated and naïve control animals (not shown).
Conclusions: Low dose (0.3 mg/kg) treatment of mice with GS-9620 induced hepatic expression of MX1, OAS1, and ISG15 in animals with undetectable IFN-α in serum. These results suggest that a low oral dose of selective TLR7 agonist can achieve immune activation in the liver in the absence of high systemic levels of IFN-α.