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标题: [AASLD2015](2007)TKM-HBV,新型RNA干扰治疗 慢性乙型肝炎,迅速降 [打印本页]

作者: StephenW    时间: 2015-10-4 15:47     标题: [AASLD2015](2007)TKM-HBV,新型RNA干扰治疗 慢性乙型肝炎,迅速降

本帖最后由 StephenW 于 2015-10-4 15:49 编辑

2007
TKM-HBV, a Novel RNA Interference Treatment for
Chronic Hepatitis B, Rapidly Reduces Surface Antigen
and other Viral Proteins in both Intrahepatic and Peripheral
Compartments
Amy C. Lee, Emily P. Thi, Luying Pei, Xin Ye, Jennifer Cross,
Sandie Y. Du, Ammen P. Dhillon, Janet R. Phelps, Kevin McClintock,
Michael Abrams, Ian MacLachlan; Tekmira Pharmaceuticals,
Burnaby, BC, Canada
TKM-HBV is a novel RNA interference (RNAi) therapeutic intervention
against hepatitis B virus (HBV) and currently in Phase 1
clinical development. It is designed to reduce the viral antigen
load in chronically infected patients and allow the body to
escape the state of immune repression imposed by the virus.
A mixture of three different oligonucleotide duplexes encapsulated
within a lipid nanoparticle delivery system, TKM-HBV acts
directly on all HBV RNAs (pregenomic RNA as well as viral
mRNA) via nucleotide sequence-specific cleavage. Because it
prevents the synthesis of viral proteins and reduces the overall
antigen load in the body, this mode of drug action may
present advantages over other approaches that seek to block
viral protein secretion into the bloodstream thereby potentially
causing intracellular build-up and ER stress. A hydrodynamic
injection (HDI) immunodeficient NOD.CB17-Prkdcscid/J mouse
model of HBV was used to characterize viral RNA targeting
and the time course of viral antigen reduction following a single
administration of TKM-HBV and its effective distribution
to its target organ, the liver. HBV RNA was measured using
branched DNA assays, HBV DNA was quantitated via QPCR,
and HBV proteins were detected using ELISA and immunohistochemistry
methods. Over 92% reduction of total HBV RNA in
the liver was observed as soon as 2 days after treatment, with
a slightly more moderate effect on the 3.5 kb species alone
suggesting this molecule is less accessible to the cellular RNAi
machinery than other HBV transcripts. Onset of serum HBV
DNA reduction was also highly rapid, with the nadir of >98%
inhibition detected at Day 2. Maximal treatment effects were
essentially reached at Day 4 for intrahepatic and serum HBsAg
(98% and 97%, respectively) whereas reduction of intrahepatic
HBcAg appeared to be a more gradual process, continuing to
decrease beyond Day 4 with a nadir reached at Day 7. Taken
together, these data suggest that the peripheral compartment is
a dynamic environment with rapid turnover of viral markers in
the blood stream whereas the turnover of viral proteins within
the intracellular compartment of liver cells occurs more slowly.
The kinetics of viral marker turnover may differ in a more
immunocompetent system. In summary, TKM-HBV effectively
removed viral antigens from both the intrahepatic and peripheral
compartments within days after a single treatment dose
in HDI mice. These viral elements include immunomodulatory
surface and core proteins which are implicated in mediating
the immune-repressed condition of chronic HBV infection.
Disclosures:
Amy C. Lee - Employment: Tekmira
Emily P. Thi - Employment: Tekmira Pharmaceuticals
Xin Ye - Employment: Tekmira Pharmaceuticals Corporation
Kevin McClintock - Employment: Tekmira Pharmaceuticals, Tekmira Pharmaceuticals,
Tekmira Pharmaceuticals, Tekmira Pharmaceuticals
The following authors have nothing to disclose: Luying Pei, Jennifer Cross, Sandie
Y. Du, Ammen P. Dhillon, Janet R. Phelps, Michael Abrams, Ian MacLachlan

作者: StephenW    时间: 2015-10-4 15:48

2007
TKM-HBV,新型RNA干扰治疗
慢性乙型肝炎,迅速降低表面抗原
并在这两个肝内和外设其它病毒蛋白
车厢
艾米C.李,艾米莉P.氏,绿营高培,鑫烨,珍妮弗·克罗斯
三叠泉Y.杜,艾门AMMEN P. Dhillon,珍妮特·R·菲尔普斯,凯文·麦克林托克,
迈克尔·艾布拉姆斯,伊恩·麦克拉克伦; Tekmira制药,
本那比,BC,加拿大
TKM - HBV是一种新颖的RNA干扰(RNAi)的治疗干预
抗乙型肝炎病毒(HBV)和目前在第1阶段
临床开发。它的目的是降低病毒抗原
装载在慢性感染病人和允许身体
逃避免疫抑制的病毒所施加的状态。
三种不同的寡核苷酸双链封装的混合物
一个脂质纳米粒传输系统中,TKM-HBV作用
直接在所有的HBV的RNA(前基因组RNA以及病毒
mRNA)的通过碱基序列特异性切割。因为它
防止病毒蛋白的合成,降低了整体
抗原负载在体内,药物作用这种模式可能
相对于其它方法目前的优势,设法阻止
病毒蛋白分泌到血液中,从而潜在地
使细胞内的积聚和内质网应激。流体动力
注(HDI)免疫NOD.CB17-Prkdcscid / J鼠标
用HBV模型来描述靶向病毒RNA
和病毒抗原减少的时间过程以下单
TKM-HBV的管理和有效配置
与其靶器官,肝脏。使用HBV RNA测定
支链DNA检测,HBV DNA是通过定量PCR定量,
并用ELISA,免疫组化检测HBV蛋白
的方法。超过92%减少总HBV RNA的
肝脏观察作为处理后尽快2天,用
在仅3.5 kb的品种稍微温和的影响
这表明该分子是不易进入至蜂窝的RNAi
机械比其他HBV成绩单。血清HBV发作
DNA减少也是非常迅速,> 98%的最低点
在第2天最大的治疗效果检测抑制分别为
在4天基本上达到肝内和血清HBsAg
(分别为98%和97%,),而减少的肝内
核心抗原似乎是更渐进的过程,持续
减少超过4天用在7日拍摄到了最低点
总之,这些数据表明,外周隔室是
随着病毒标志物快速周转的动态环境
血流而病毒蛋白的内周转
肝细胞的细胞内隔室发生更缓慢。
病毒标志物的营业额的动力学可能不同更
免疫系统。综上所述,TKM-HBV有效
同时从肝内和外围除去病毒抗原
单次治疗剂量后几天内室
在HDI小鼠。这些病毒的因素包括免疫调节
这是参与介导表面和核心蛋白
慢性HBV感染的免疫抑制状态。
披露:
艾米C.李 - 就业:Tekmira
艾米莉P.氏 - 就业:Tekmira制药
鑫烨 - 就业:Tekmira制药公司
凯文·麦克林托克 - 就业:Tekmira制药,Tekmira制药,
Tekmira制药,Tekmira制药
下面笔者都没有透露:绿营高陂,詹妮弗十字,桑迪
Y.杜,艾门AMMEN P. Dhillon,珍妮特·R·菲尔普斯,迈克尔·艾布拉姆斯,伊恩·麦克拉克伦
作者: zgct    时间: 2015-10-4 20:45

本帖最后由 zgct 于 2015-10-4 20:46 编辑

谢谢,有讲到可以很好干掉integrated DNA”
作者: zgct    时间: 2015-10-4 20:48

谢谢,有讲到可以很好干掉整合到肝细胞内HBV的基因吗?integrated DNA?

作者: StephenW    时间: 2015-10-4 22:19

zgct 发表于 2015-10-4 20:48
谢谢,有讲到可以很好干掉整合到肝细胞内HBV的基因吗?integrated DNA?

这只有在小鼠(特种)中测试.
integrated DNA 发现在感染和NUC治疗的黑猩猩中.





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