瞄准赖氨酰氧化酶抑制胶原蛋白的交联和加速预先建立肝纤

StephenW

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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.
>

StephenW

瞄准赖氨酰氧化酶抑制胶原蛋白的交联和加速预先建立肝纤维化的逆转

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>记者朱莱
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> AASLD 2013 11月1-4洗DC
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直树Ikenaga1 ，田修平Yoshida1 ，苏珊·B·柳1 ， Jeanhee Chung1 ，迪安娜Sverdlov1 ，德里克Marshall2 ，维维安Barry2 ，维多利亚Smith2 ，玛丽亚Kovalenko2 ，萨蒂亚吉特Karnik2 ， NEZAM H. Afdhal1 ， Popov1尤里
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>胃肠病学和肝病贝丝以色列女执事医疗中心，哈佛大学医学院，波士顿， MA ， 2Gilead科学，加利福尼亚州福斯特城， 1区
> AASLD ：赖氨酰氧化酶选择性抑制像2 （ LOXL2 ）使用的治疗性单克隆抗体抑制胆管纤维化的进展，新的PSC-小鼠模型一样 - （ 13年11月13日）
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> 64rd的肝脏疾病研究协会的年度会议
>华盛顿特区， 11月1-5 2013
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>结论
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>延迟治疗与反LOXL2抗体是有效的
> suppresing胶原交联和纤维化
>在体内级数。
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> LOXL2抑制加速肝纤维化分辨率
在TAA -纤维化早期恢复模式。
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目前正在努力，以评估治疗
>肝病针对LOXL2的疗效
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> PROGRAM摘要：
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>背景/目的：越来越多的证据表明，预先存在的慢性丙型肝炎引起的肝硬化赋予即使在病毒已经成功地消除了长期患肝癌。我们以前发现，转谷氨酰胺酶独立胶原交联延缓肝硬化逆转。在本研究中，我们测试是否胶原蛋白交联，可以成功地抑制扭转利用针对LOXL2 ，与赖氨酰氧化酶的活性在小鼠模型中诱导蛋白的抗体，该抗体在体内的晚期纤维化。
方法：晚期肝纤维化诱导C57BL / 6小鼠反复注射硫代乙酰胺（ TAA ） 。的新型反LOXL2的治疗的的抗体（ AB0023mAB ， 30mg/kg时）或控制抗体（M64 ， 30mg/kg时）管理IP每周两次纤维化的进展过程中（延迟治疗，从第6周12 TAA ） ，或在肝纤维化逆转（ 1至12周后恢复， TAA） （N = 10-16元组） 。胶原交联，使用阶梯状的胶原的提取/分馏方法，评估体外。
>结果：免疫组化分析显示， LOXL2几乎不存在健康的肝脏，但强烈诱导在TAA-诱导的肝纤维化，纤维间隔内主要定位。的延迟反LOXL2的治疗预先建立的，先进的肝纤维化（周6至12 TAA ）抑制纤维化矩阵的稳定，高度交联的胶原分数减少了30％ 。桥接纤维化的病理体征改善，净胶原沉积减少25％ ，生化评估在LOXL2组通过羟脯氨酸（P = 0.025 ） 。当LOXL2抑制纤维化恢复过程中，深刻加速重塑纤维间隔观察，变薄和分裂的胶原纤维组织，肝胶原蛋白水平下降36 ％ （ P = 0.021） ，峰值在早期的恢复时间点（ 4周） 。与此相反，没有显着的影响，胶原蛋白交联，纤维化的进展，或反转检测到使用对照抗体处理的小鼠组织学或生物化学的方法。
结论： 1 ）抗体介导的LOXL2抑制有效抑制胶原蛋白的交联体内实验性肝纤维化的进展过程中。 2 ） LOXL2抑制迅速和有力地加速肝纤维化的分辨率从TAA损伤的恢复模型。 3 ）可行性的抗体靶向LOXL2防止和扭转肝硬化应在今后的临床试验进行评估。
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