核酸聚合物REP 2139和核苷（t）ide类似物对体内慢性肝炎病毒

StephenW

Hepatology. 2017 Dec 18. doi: 10.1002/hep.29737. [Epub ahead of print]
Nucleic acid polymer REP 2139 and nucleos(t)ide analogues act synergistically against chronic hepadnaviral infection in vivo.
Quinet J1, Jamard C1, Burtin M1, Lemasson M2, Guerret S3, Sureau C2, Vaillant A4, Cova L1.
Author information

1
    Institut National de Santé et Recherche Médicale (INSERM) U1052, Lyon.
2
    Institut National de la Transfusion Sanguine (INTS), Paris, France.
3
    Novotec, Lyon, France.
4
    Replicor Inc. Montreal, Canada, H4P 2R2.

Abstract

Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in DHBV-infected ducks and in patients with chronic HBV or HBV/HDV infection. In this preclinical study, a novel combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139-Ca; TDF; REP 2139-Ca + TDF; REP 2139-Ca + TDF + ETV. After 4-weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti DHBsAg antibodies (anti-DHBs) were monitored by ELISA and viremia by qPCR. Total viral DNA and cccDNA were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow-up by immunohistochemistry. On-treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (> 3log) and cccDNA (> 2log), which were tightly correlated with the clearance of DHBsAg in the liver.
CONCLUSION:

Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. This article is protected by copyright. All rights reserved.

© 2017 by the American Association for the Study of Liver Diseases.
KEYWORDS:

Combination therapy; Hepatitis B Virus (HBV); Nucleic acid polymer (NAP); nucleos(t)ide analogs (NUCs)

PMID:
    29251788
DOI:
    10.1002/hep.29737

StephenW

肝病。 2017 Dec 18。doi：10.1002 / hep.29737。 [电子版提前打印]
核酸聚合物REP 2139和核苷（t）ide类似物对体内慢性肝炎病毒感染起协同作用。
Quinet J1，Jamamad C1，Burtin M1，Lemasson M2，Guerret S3，Sureau C2，Vaillant A4，Cova L1。
作者信息

1
    Institut National deSantéet RechercheMédicale（INSERM）U1052，Lyon。
2
    Institut National de la Transfusion Sanguine（INTS），Paris，France。
3
    Novotec，法国里昂。
4
    Replicor Inc.加拿大蒙特利尔H4P 2R2。

抽象

显示核酸聚合物（NAP）REP 2139处理阻断DHBV感染的鸭中和慢性HBV或HBV / HDV感染患者中的病毒表面抗原的释放。在此临床前研究中，在慢性DHBV感染模型中评估了由REP 2139与替诺福韦二吡呋酯富马酸盐（TDF）和恩替卡韦（ETV）组成的新型组合疗法体内评估。 DHBV感染的鸭组如下处理：生理盐水（对照）; REP 2139-Ca; TDF; REP 2139-Ca + TDF; REP 2139-Ca + TDF + ETV。治疗4周后，所有动物随访8周。通过ELISA监测血清DHBsAg和抗DHBsAg抗体（抗DHBs），并通过qPCR监测病毒血症。通过qPCR在尸检肝脏样品中定量总病毒DNA和cccDNA。在随访结束时通过免疫组织化学评估肝内DHBsAg。当REP 2139联合TDF或TDF和ETV时，治疗中血清DHBsAg和病毒血症的减少更为迅速，与TDF单药治疗相比，治疗停止后没有观察到病毒反弹。重要的是，联合治疗导致肝内病毒DNA（> 3log）和cccDNA（> 2log）的显着降低，这与DHBsAg在肝脏中的清除密切相关。
结论：

当REP 2139与TDF或TDF + ETV组合时，观察到协同抗病毒作用，导致血液和肝脏中的感染控制，与撤除治疗后持续存在的肝内病毒表面抗原消除相关。我们的研究结果表明，在没有聚乙二醇化干扰素的情况下，开发这种联合疗法治疗慢性感染患者的潜力。本文受版权保护。版权所有。

©2017由美国肝病研究协会。
关键词：

联合治疗;乙型肝炎病毒（HBV）;核酸聚合物（NAP）;核苷（酸）类似物（NUC）

结论：
    29251788
DOI：
    10.1002 / hep.29737

hp121

回复 StephenW 的帖子

这怎么又走回来了？？

又是做鸭子实验了？？

纯属研究性质？？还是从动物实验开始，再一期二期三期临床？？那又是遥遥无期了

newchinabok

回复 hp121 的帖子

这是个古老的传说，可笑的是还有许许多多听众

StephenW

回复 hp121 的帖子

这个问题之前问过, 没有正式的理由.我自己的猜测是:
批准新药，FDA喜欢动物研究，最重要的是药物为什么起作用.

hp121

回复 newchinabok 的帖子

现在还说不好

只能说，也许成功率不高