The studies titled Heparc-2002 and Heparc-2003 will enroll patients with chronic HBV infection that are e-antigen (HBeAg) negative and HBeAg positive, respectively. Each study is a multicenter, randomized, double-blind, placebo-controlled, multi-dose study intended to evaluate two dose levels in parallel of ARC-520 in combination with entecavir or tenofovir in patients with immune active chronic HBV infection. The 2002 and 2003 studies are planned to enroll up to 60 and 90 patients, respectively. In each study, patients will be randomized to receive four doses, once every 4 weeks, of either 1 mg/kg ARC-520, 2 mg/kg ARC-520, or placebo at a ratio of 1:1:1.作者: newchinabok 时间: 2015-6-19 22:01
The goal is to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without sero-conversion.
Current treatment options include interferon, which is difficult to use due to highly disruptive side effects, and nucleotide or nucleoside analogues, referred to collectively as NUCs. The best NUCs are very good at suppressing viremia, the production and release of new viral particles, but are not capable of directly suppressing the production and release of viral proteins including s-antigen and e-antigen. Neither interferon nor NUCs provide meaningful rates of functional cure.
ARC-520 uses a different mechanism than NUCs
RNAi in general, and the siRNAs in ARC-520 specifically, act in a fundamentally different way than NUCs. These siRNAs intervene at the mRNA level, upstream of where nucleotide and nucleoside analogues act, and have been shown to deeply knock down all HBV gene products, including proteins and the viral intermediates necessary to produce viral DNA. Many experts in the field believe that knocking down key viral antigens may revive the host adaptive immune response and potentially achieve a functional cure.作者: zgct 时间: 2015-6-20 21:26
RNAi delivery approaches include conjugates, liposomal nanoparticles (LNPs), and viral vectors. Nanoparticles deliver synthetic dsRNA, whereas viral vectors deliver a transcriptional template to the nucleus. Cellular uptake occurs nonspecifically or via receptor-mediated endocytosis. Nanoparticles deliver the RNAi trigger to the cytoplasm. The trigger enters the RNAi pathway at the RISC or Dicer processing stage. Transcriptional templates produce hairpin RNAs that enter the pathway at an earlier, nuclear stage. Ultimately, an active RISC complex is formed that cleaves the mRNA target.
RISC, RNA-induced silencing complex; shRNA, short hairpin-mediated RNA.
RNAi的递送方法包括偶联物,脂质体纳米颗粒(岭澳核电站),和病毒载体。纳米粒子递送合成的双链RNA,而病毒载体递送的转录模板到细胞核。发生非特异性或通过受体介导的内吞作用的细胞摄取。纳米粒子递送所述RNAi触发到细胞质。触发进入RNAi途径在RISC或切酶处理阶段。转录模板产生进入途径在较早,核级发夹RNA。最终,活性RISC复合物所形成的切割的mRNA靶。 RISC,RNA诱导沉默复合体; shRNA的短发夹RNA介导的。作者: StephenW 时间: 2015-6-21 07:13