studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 881A
1367
Dual combination therapy directed against lysyl oxidase-like
2 (LOXL2) and apoptosis signal-regulating
kinase 1 (ASK1) potently inhibits fibrosis and portal
hypertension in a new mouse model of PSC-like liver
disease
Naoki Ikenaga 1 , Susan B. Liu 1 , Zhen-Wei Peng 1 , Andrew E.
Greenstein 2 , Dorothy French 2 , Victoria Smith 2 , Yury Popov 1 ;
1 Gatroenterology, Beth Israel Deaconnes, Boston, MA; 2 Gilead
Sciences, Inc, Foster City, CA
BACKGROUND/AIMS: We have previously characterized
novel LOXL2 and ASK1 inhibitors as effective monotherapies
for liver fibrosis in vitro and in vivo. They impact distinct,
non-overlapping pro-fibrogenic signal transduction pathways,
with LOXL2 mediating collagen cross-linking and ASK1 promoting
hepatocyte injury and fibrogenic stellate cell activation
via the p38 and JNK pathways. Here, the therapeutic efficacy
of combined anti-LOXL2 and anti-ASK1 agents was evaluated
in a mouse model of biliary fibrosis and portal hypertension.
METHODS: We developed an improved BALBc.Mdr2-/- mouse
model resembling human primary sclerosing cholangitis (PSC)
with rapidly progressive fibrosis and early-onset portal hypertension
(Ikenaga et al, 2015). 6 weeks of ASK1 inhibitor (GS-
444217, 0.15% in diet), anti-LOXL2 monoclonal antibody
(AB0023 mAb/GS-607601, 30mg/kg/week i/p), or their
combination were administered to 6 weeks old BALB/c.Mdr2-
/- mice with pre-established fibrosis (n=9-11/group). Portal
venous pressure (PVP) was measured via direct cannulation of
the portal vein with a micro-tip pressure monitor at the end of
the study. Liver fibrosis was evaluated by histology and biochemical
determination of collagen. RESULTS Both anti-LOXL2
and anti-ASK1 mono-therapies significantly improved histological
signs of fibrosis, with reduced hepatic collagen deposition
(by 37 and 38% of hydroxyproline, respectively) in BALB/c.
Mdr2-/- mice compared to placebo control group (p