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> Targeting lysyl oxidase like 2 (LOXL2) inhibits collagen cross-linking and accelerates reversal of pre-established liver fibrosis
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> Reported by Jules Levin
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> AASLD 2013 Nov 1-4 Wash DC
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> Naoki Ikenaga1, Shuhei Yoshida1, Susan B. Liu1, Jeanhee Chung1, Deanna Sverdlov1, Derek Marshall2, Vivian Barry2, Victoria Smith2, Maria Kovalenko2, Satyajit Karnik2, Nezam H. Afdhal1, Yury Popov1
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> 1Division of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 2Gilead Sciences, Foster City, CA
> AASLD: Selective inhibition of lysyl oxidase like 2 (LOXL2) using a therapeutic monoclonal antibody suppresses the progression of biliary fibrosis in novel PSC-like mouse model - (11/13/13)
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> 64rd Annual Meeting of the American Association for the Study of Liver Diseases
> Washington, DC Nov 1-5 2013
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> CONCLUSIONS
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> Delayed treatment with anti-LOXL2 antibody is effective
> in suppresing collagen cross-linking and fibrosis
> progression in vivo.
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> LOXL2 inhibition accelerated hepatic fibrosis resolution
> in the early stage recovery model from TAA-fibrosis.
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> Currently efforts are underway to evaluate therapeutic
> efficacy of targeting LOXL2 in liver disease
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> PROGRAM ABSTRACT:
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> BACKGROUND/AIMS: Emerging evidence suggests that pre-existing cirrhosis caused by chronic hepatitis C confers long-term risk of liver cancer even after the virus has been successfully eliminated. We previously showed that transglutaminase-independent collagen cross-linking retards liver cirrhosis reversal. In this study, we test whether collagen cross-linking can be successfully inhibited to reverse advanced fibrosis in vivo utilizing an antibody directed against LOXL2, an inducible protein with lysyl oxidase activity in mouse models.
> METHODS: Advanced liver fibrosis was induced in C57Bl/6 mice by repeated injections of thioacetamide (TAA). Novel anti-LOXL2 therapeutic antibody (AB0023mAB, 30mg/kg) or control antibody (M64, 30mg/kg) was administered i.p. twice a week (n=10-16 per group) during fibrosis progression (delayed treatment, from week 6 to 12 of TAA) or during fibrosis reversal (recovery, 1 to 12 weeks after TAA). Collagen cross-linking was assessed ex vivo using a step-wise collagen extraction/fractionation method.
> RESULTS: Immunohistochemical analysis revealed that LOXL2 was virtually absent from healthy liver, but was strongly induced in TAA-induced fibrotic liver, with predominant localization within fibrotic septa. Delayed anti-LOXL2 treatment of pre-established, advanced liver fibrosis (week 6 through 12 of TAA) inhibited fibrotic matrix stabilization, with a 30% reduction in the highly cross-linked collagen fraction. Histological signs of bridging fibrosis improved, with a 25% decrease in net collagen deposition in LOXL2-treated group as assessed biochemically via hydroxyproline (p=0.025). When LOXL2 was inhibited during fibrosis recovery, profound acceleration of remodeling of fibrotic septa was observed, with thinning and splitting of collagen fibrils histologically, and a 36% decrease in hepatic collagen levels (p=0.021) peaking at the early recovery time-point (4 weeks). In contrast, no significant effect on collagen cross-linking, fibrosis progression, or reversal was detected using histological or biochemical methods in control antibody -treated mice.
> CONCLUSIONS: 1) Antibody-mediated LOXL2 inhibition effectively suppressed collagen cross-linking during experimental liver fibrosis progression in vivo. 2) LOXL2 inhibition rapidly and potently accelerated hepatic fibrosis resolution in the recovery model from TAA-injury. 3) Feasibility of antibody targeting of LOXL2 to prevent and reverse liver cirrhosis should be evaluated in future clinical trials.
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