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.
Ok good results as always but an update on human trials?? i think they have tested the drug on healthy volounteers on an early phase I but they go on with reports on mice. I really dont understand this...
What I don't understand s WHY they are still testing this stuff on mice? What about just giving it to people? Cancer patients what tolerate up to 20 mg of this stuff? So Why not give us 7-10mg and and see what happens in six months. Today these companies can do real world clinical trials and really help people right here on line on these forums.
But we have nobody from Gilead come here and at least SPEAK with us.
Off course it is the immune system that clears HBV, Boosting it should have be the strategy all along. Instead of giving drugs that used to slow down cancer and HIV. We don't need that we need immune activation not suppression to clear HBV..
So at least Gilead is moving in the right direction. And I think they have something there, at least it will be better then these dangerous nucs that some of us took for so many years.
So it would be really nice if somebody from Gilead come here and really talk about the medication. And extend/open the doors to the people that desperately need more effective treatment.
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