AASLD2018[450]Galxc™RNAi的临床前特征 针对不同地区的治疗药物 H

StephenW

450
Preclinical Characterization of Galxc™ RNAi
Therapeutics Targeting Different Regions of the
HBV Genome
Martin Koser1, Kevin P. Craig2, Wendy A. Cyr3, Weimin Wang2,
Bob D. Brown2 and Marc Abrams1, (1)Preclinical Development,
Dicerna Pharmaceuticals, (2)Dicerna Pharmaceuticals, (3)
Program Development, Dicerna Pharmaceuticals
Background: Chronic Hepatitis B Virus (HBV) infection
is a significant cause of worldwide morbidity and mortality;
currently available medications do not enable functional cure.
RNA interference (RNAi) technology can pharmacologically
intervene at every stage of the viral life cycle, including
production of viral antigens from its cccDNA (covalently
closed circular DNA) form and integrated genomes. GalXC
technology represents a novel structural class of systemicallyadministered,
hepatocyte-targeting RNAi therapeutics.
We sought to use the GalXC platform to investigate the
pharmacodynamic response to RNAi agents targeting
different regions of the viral genome. Methods: RNAi
conjugates targeting the HBV Surface Antigen (HBsAg) open
reading frame were compared to RNAi conjugates targeting
the HBV-X open reading frame, or to a combination of both
agents. The compounds were administered subcutaneously
into mice expressing the HBV genome. Magnitude and
duration of HBsAg inhibition served as the primary endpoint.
Subcellular localization of HBV Core Antigen (HBcAg) was
also evaluated. Results: GalXC agents targeting within the
HBsAg coding region displayed superior duration of activity
compared to those targeting within HBV-X or the combination.
Interestingly, only the HBsAg-targeted oligonucleotide
inhibited accumulation of nuclear HBcAg, an indicator of
cccDNA transcriptional activity. The mechanistic model for
these observations will be discussed. Conclusion: Different
HBV RNAi target sites demonstrate strikingly different
pharmacodynamic properties. These data strongly support
clinical evaluation of GalXC-HBVS, a development-stage
investigational RNAi therapeutic targeting HBsAg.
Disclosures:
Martin Koser – Dicerna Pharmaceuticals: Employment
Marc Abrams – Dicerna Pharmaceuticals: Employment; Dicerna
Pharmaceuticals: Stock Shareholder
Disclosure information not available at the time of publication: Kevin P. Craig,
Wendy A. Cyr, Weimin Wang, Bob D. Brown

StephenW

450
Galxc™RNAi的临床前特征
针对不同地区的治疗药物
HBV基因组
Martin Koser1，Kevin P. Craig2，Wendy A. Cyr3，Weimin Wang2，
Bob D. Brown2和Marc Abrams1，（1）临床前开发，
Dicerna Pharmaceuticals，（2）Dicerna Pharmaceuticals，（3）
程序开发，Dicerna Pharmaceuticals
背景：慢性乙型肝炎病毒（HBV）感染
是全球发病率和死亡率的重要原因;
目前可用的药物不能实现功能性治愈。
RNA干扰（RNAi）技术可以在药理学上进行
干预病毒生命周期的每个阶段，包括
从其cccDNA产生病毒抗原（共价
封闭的环状DNA）形式和整合的基因组。 GalXC
技术代表了系统管理的新型结构类，
肝细胞靶向RNAi治疗剂。
我们试图使用GalXC平台来调查
对RNAi剂靶向的药效学反应
病毒基因组的不同区域。方法：RNAi
靶向HBV表面抗原（HBsAg）的结合物打开
将阅读框与靶向的RNAi结合物进行比较
HBV-X开放式阅读框，或两者兼而有之
代理商。皮下给予化合物
进入表达HBV基因组的小鼠。幅度和
HBsAg抑制的持续时间作为主要终点。
HBV核心抗原（HBcAg）的亚细胞定位为
也评估。结果：GalXC药剂靶向内
HBsAg编码区显示出优越的活动持续时间
与HBV-X或其组合中的靶向相比。
有趣的是，只有HBsAg靶向的寡核苷酸
抑制核HBcAg积累，一个指标
cccDNA转录活性。机械模型
将讨论这些观察结果。结论：不同
HBV RNAi靶位点表现出惊人的差异
药效学特性。这些数据强烈支持
GalXC-HBVS的临床评估，一个发展阶段
针对HBsAg的研究性RNAi治疗药物。
披露：
Martin Koser - Dicerna Pharmaceuticals：就业
Marc Abrams - Dicerna Pharmaceuticals：就业; Dicerna
制药：股东
发布时无法提供的披露信息：Kevin P. Craig，
Wendy A. Cyr，Weimin Wang，Bob D. Brown

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Galxc™RNAi的临床前特征

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Conclusion: Different
HBV RNAi target sites demonstrate strikingly different
pharmacodynamic properties. These data strongly support
clinical evaluation of GalXC-HBVS, a development-stage
investigational RNAi therapeutic targeting HBsAg.

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rnai技术已经进入百花齐放阶段