EASL2015:治疗作用反对各种乙型肝炎 核酸慢性乙型肝炎病毒感

StephenW

P0542
THERAPEUTIC EFFECT AGAINST HEPATITIS B OF VARIOUS
NUCLEIC ACID POLYMERS IN THE CHRONIC DHBV INFECTION
MODEL
C. Brikh1, C. Jamard1, J. Quinet1, C. Bouchareb1, I. Roehl2,
A. Vaillant3, L. Cova1. 1CRCL, INSERUM U1052, University Lyon 1,
Lyon, France; 2Axolabs GMBH, Kulmbach, Germany; 3REPLICor Inc.,
Montreal, Canada
E-mail: [email protected]
Background and Aims: Nucleic acid polymers (NAPs) block the
release of HBsAg from infected hepatocytes and can effectively clear
the blood of HBsAg in human subjects with chronic HBV infection.
When used in combination with immunotherapy, NAPs can achieve
higher SVR rates in patients than when immunotherapy is used
alone. The goal of this preclinical study was to examine the effect of
various NAP modifications on their tolerability, liver accumulation
and antiviral effect in vivo in the chronic DHBV infection model.
Methods: Three-day-old Pekin ducklings were infected with
infectious duck serum (2×1011 VGE/ml of DHBV). NAP treatment
was started in 14 day old animals via intraperitoneal injection
with 10 mg/kg of NAPs 3 times / week for three weeks followed
by autopsy analysis. All five NAPs used (REP 2055, REP 2139, REP
2163, REP 2165 and REP 2166) had the same sequence composition
([AC]20) but each comprised different modifications impacting
the tolerability and stability of oligonucleotides. Tolerability was
assessed by monitoring weight during treatment, injection site
reactivity and findings at autopsy. NAP levels in the liver at the
end of treatment were assessed by fluorescence-HPLC using a
fluorescent PNA probe-based hybridization assay. Antiviral activity
was assessed by monitoring serum DHBsAg and anti-DHBpreS
antibodies by ELISA and serum and liver DHBVDNA by quantitative
PCR.
Results: No significant changes in weight gain or injection site
reactions were observed for any NAP. All NAPs tested reduced serum
DHBsAg and this effect was more pronounced with REP 2055, REP
2139, REP 2163 and REP 2165. The most significant stimulation of
anti-DHBpreSAg antibody response was observed in the REP 2139
and REP 2165 groups. Substantial reductions in serum DHBVDNA
were found in all NAP groups. Drastic decrease in liver DHBVDNA
was observed for four groups treated with REP 2055, REP 2139,
REP 2163 and REP 2165. Importantly, liver accumulations for some
NAPs that were less resistant to nuclease attack (REP 2055 and REP
2165) were 6–7 fold less at the end of treatment than for REP 2139
yet showed comparable antiviral activity.
Conclusions: The tolerability and liver accumulation of NAPs can
be modulated significantly without affecting their overall ability to
reduce serum DHBsAg and elicit other crucial antiviral responses
in DHBV-carriers, suggesting important ways in which NAPs can be
altered to minimize side effects and liver accumulation in human
subjects receiving NAP therapy

StephenW

Showing translation for P0542 THERAPEUTIC EFFECT AGAINST HEPATITIS B OF VARIOUS NUCLEIC ACID POLYMERS IN THE CHRONIC DHBV INFECTION MODEL C. Brikh1, C. Jamard1, J. Quinet1, C. Bouchareb1, I. Roehl2, A. Vaillant3, L. Cova1. 1CRCL, INSERUM U1052, University Lyon 1, Lyon, France; 2 Axolabs GMBH, Kulmbach, Germany; 3REPLICor Inc., Montreal, Canada E-mail: [email protected] Background and Aims: Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes and can effectively clear the blood of HBsAg in human subjects with chronic HBV infection. When used in combination with immunotherapy, NAPs can achieve higher SVR rates in patients than when immunotherapy is used alone. The goal of this preclinical study was to examine the effect of various NAP modifications on their tolerability, liver accumulation and antiviral effect in vivo in the chronic DHBV infection model. Methods: Three-day-old Pekin ducklings were infected with infectious duck serum (2×1011 VGE/ml of DHBV). NAP treatment was started in 14 day old animals via intraperitoneal injection with 10 mg/kg of NAPs 3 times / week for three weeks followed by autopsy analysis. All five NAPs used (REP 2055, REP 2139, REP 2163, REP 2165 and REP 2166) had the same sequence composition ([AC]20) but each comprised different modifications impacting the tolerability and stability of oligonucleotides. Tolerability was assessed by monitoring weight during treatment, injection site reactivity and findings at autopsy. NAP levels in the liver at the end of treatment were assessed by fluorescence-HPLC using a fluorescent PNA probe-based hybridization assay. Antiviral activity was assessed by monitoring serum DHBsAg and anti-DHBpreS antibodies by ELISA and serum and liver DHBVDNA by quantitative PCR. Results: No significant changes in weight gain or injection site reactions were observed for any NAP. All NAPs tested reduced serum DHBsAg and this effect was more pronounced with REP 2055, REP 2139, REP 2163 and REP 2165. The most significant stimulation of anti-DHBpreSAg antibody response was observed in the REP 2139 and REP 2165 groups. Substantial reductions in serum DHBVDNA were found in all NAP groups. Drastic decrease in liver DHBVDNA was observed for four groups treated with REP 2055, REP 2139, REP 2163 and REP 2165. Importantly, liver accumulations for some NAPs that were less resistant to nuclease attack (REP 2055 and REP 2165) were 6–7 fold less at the end of treatment than for REP 2139 yet showed comparable antiviral activity. Conclusions: The tolerability and liver accumulation of NAPs can be modulated significantly without affecting their overall ability to reduce serum DHBsAg and elicit other crucial antiviral responses in DHBV-carriers, suggesting important ways in which NAPs can be altered to minimize side effects and liver accumulation in human subjects receiving NAP therapy
Translate instead from P0542 THERAPEUTIC EFFECT AGAINST HEPATITIS B OF VARIOUS NUCLEIC ACID POLYMERS IN THE CHRONIC DHBV INFECTION MODEL C. Brikh1, C. Jamard1, J. Quinet1, C. Bouchareb1, I. Roehl2, A. Vaillant3, L. Cova1. 1CRCL, INSERUM U1052, University Lyon 1, Lyon, France; 2Axolabs GMBH, Kulmbach, Germany; 3REPLICor Inc., Montreal, Canada E-mail: [email protected] Background and Aims: Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes and can effectively clear the blood of HBsAg in human subjects with chronic HBV infection. When used in combination with immunotherapy, NAPs can achieve higher SVR rates in patients than when immunotherapy is used alone. The goal of this preclinical study was to examine the effect of various NAP modifications on their tolerability, liver accumulation and antiviral effect in vivo in the chronic DHBV infection model. Methods: Three-day-old Pekin ducklings were infected with infectious duck serum (2×1011 VGE/ml of DHBV). NAP treatment was started in 14 day old animals via intraperitoneal injection with 10 mg/kg of NAPs 3 times / week for three weeks followed by autopsy analysis. All five NAPs used (REP 2055, REP 2139, REP 2163, REP 2165 and REP 2166) had the same sequence composition ([AC]20) but each comprised different modifications impacting the tolerability and stability of oligonucleotides. Tolerability was assessed by monitoring weight during treatment, injection site reactivity and findings at autopsy. NAP levels in the liver at the end of treatment were assessed by fluorescence-HPLC using a fluorescent PNA probe-based hybridization assay. Antiviral activity was assessed by monitoring serum DHBsAg and anti-DHBpreS antibodies by ELISA and serum and liver DHBVDNA by quantitative PCR. Results: No significant changes in weight gain or injection site reactions were observed for any NAP. All NAPs tested reduced serum DHBsAg and this effect was more pronounced with REP 2055, REP 2139, REP 2163 and REP 2165. The most significant stimulation of anti-DHBpreSAg antibody response was observed in the REP 2139 and REP 2165 groups. Substantial reductions in serum DHBVDNA were found in all NAP groups. Drastic decrease in liver DHBVDNA was observed for four groups treated with REP 2055, REP 2139, REP 2163 and REP 2165. Importantly, liver accumulations for some NAPs that were less resistant to nuclease attack (REP 2055 and REP 2165) were 6–7 fold less at the end of treatment than for REP 2139 yet showed comparable antiviral activity. Conclusions: The tolerability and liver accumulation of NAPs can be modulated significantly without affecting their overall ability to reduce serum DHBsAg and elicit other crucial antiviral responses in DHBV-carriers, suggesting important ways in which NAPs can be altered to minimize side effects and liver accumulation in human subjects receiving NAP therapy
P0542
治疗作用反对各种乙型肝炎
核酸慢性乙型肝炎病毒感染聚合物
MODEL
C. Brikh1，C. Jamard1，J. Quinet1，C. Bouchareb1，一Roehl2，
A. Vaillant3，L. Cova1。 1CRCL，INSERUM U1052，大学里昂1，
法国里昂; 2 Axolabs GMBH，库姆巴赫，德国; 3REPLICor公司，
加拿大蒙特利尔
电子邮件：[email protected]
背景和目的：核酸聚合物（国家行动计划）阻断
从感染的肝细胞释放的HBsAg，并能有效地清除
乙肝表面抗原的慢性HBV感染人类受试者的血液。
当与免疫治疗联合使用，国家行动方案，可以实现
更高的SVR率比患者免疫治疗时使用
孤单。这种临床前研究的目的是检查的效果
在他们的耐受性，肝积累各种NAP修改
在体内，在慢性乙型肝炎病毒感染模型和抗病毒的效果。
方法：三日龄雏鸭PEKIN被感染
感染鸭血清（2×1011 VGE /毫升DHBV的）。 NAP治疗
经腹腔注射开始14天的动物
用10mg / kg的的行动方案3次/周三周，随后
经尸检分析。使用所有五个国家行动计划（REP 2055，REP 2139 REP
2163年，REP 2165和REP 2166）有相同的序列组成
（[AC] 20），但各由不同的修改影响
的耐受性和寡核苷酸的稳定性。耐受性
通过在治疗，注射部位监测评估重量
反应和尸检结果。 NAP水平在肝脏的
治疗结束通过荧光-HPLC使用评估
荧光PNA探针为基础的杂交试验。抗病毒活性
通过监测血清DHBsAg和抗DHBpreS评估
抗体通过ELISA和血清和肝脏DHBVDNA通过定量
PCR。
结果：没有显著改变体重增加或注射部位
观察任何NAP反应。所有的国家行动计划减少测试血清
DHBsAg这种效应更明显REP 2055 REP
2139，REP 2163和REP 2165最显著刺激
抗DHBpreSAg抗体应答中观察到所述REP 2139
和REP 2165组。大幅降低血清DHBVDNA
被发现在所有NAP组。肝DHBVDNA急剧下降
观察四组，REP 2055，REP 2139治疗，
REP 2163和REP 2165重要的是，肝脏积累了一些
那要攻击核酸（REP 2055和REP抗性较差的国家行动方案
2165）为6-7倍，在较低治疗结束比REP 2139
还表明可比的抗病毒活性。
结论：国家行动方案的耐受性和肝脏蓄积能
在不影响他们的整体能力显著调制
降低血清DHBsAg并征求其他重要抗病毒反应
在DHBV载波，提示重要的方法，使国家行动计划能够
改变以最小化的副作用和肝脏累积在人
接受NAP治疗科目

crysalechain

楼主，您觉得研究出治愈HBV的药至少还要等多久？？

战天斗hbv

crysalechain 发表于 2015-4-23 20:16
楼主，您觉得研究出治愈HBV的药至少还要等多久？？

我来替sw回答、sw说过、5年之内、我的见解、哥就指着birinapant了

crysalechain

这么乐观？

StephenW

回复 crysalechain 的帖子

我不知道。
几年前，我以为REP9AC将在现在提供治愈治疗. 很失望，这并未发生. 现在REP9AC从临床前研究再次开始, 我希望能够更快地批准.
长期抗病毒治疗 + 低血清HBsAg + 加干扰素 - 成功率还是太低.

crysalechain

是啊。太低了。