|
  
- 现金
- 6394 元
- 精华
- 0
- 帖子
- 3365
- 注册时间
- 2007-6-13
- 最后登录
- 2023-2-10
|
Conclusions
ARC-520 RNAi triggers were fully chemically modified to prevent cytokine induction. Fresh human whole blood was exposed to
ARC-520 at plasma equivalent exposures to intravenous doses of 2-12 mg/kg ARC-520 (20-120 µg/mL). The observed elevation of
cytokine levels, typically by a few-fold, was quite small compared to the increase in cytokine levels by 2-3 orders of magnitude in
positive controls (LPS and R848).
REFERENCES
Schluep et al. Safety, Tolerability, and
Pharmacokinetics of ARC-520 Injection, an
RNA Interference-Based Therapeutic for the
Treatment of Chronic Hepatitis B Virus
Infection, in Healthy Volunteers. Clin
Pharmacol Drug Dev. 2017; 6(4):350-62.
Wooddell et al. Hepatocyte-targeted RNAi
therapeutics for the treatment of chronic
hepatitis B virus infection. Mol Ther. 2013
May; 21(5):973-85.
Wooddell et al. RNAi-based treatment of
chronically infected patients and chimpanzees
reveals that integrated hepatitis B virus DNA is
a source of HBsAg. Sci Transl Med. 2017 Sep;
27(9):409.
The RNAi therapeutic ARC-520 caused negligible cytokine response in human whole blood and healthy volunteers (Schluep et al., 2017). Chimpanzees chronically infected with HBV had periodic serum
elevations of IFNɣ, TNFα, CXCL9, and in some animals CXCL10, throughout the study. These elevations did not coincide with injection of RNAi treatment (half-life in plasma is <8 hrs). RNAi treatment appeared
to generally reduce cytokine response but in some animals and at some times perhaps facilitated it, such as in chimp S-1 with repeatedly decreasing replication off treatment.
Pathway Analysis compares mRNA-seq gene expression data across time points to identify pathways that change by specified parameters, thereby allowing the generation of hypotheses. Dendritic cell
maturation, PKCƟ signaling in T lymphocytes, role of NFAT in regulation of the immune response and IL-8 signaling were canonical pathways activated in the 3 HBeAg-negative chimps and the HBeAgseroconverted
chimp S-1, especially when HBsAg was deeply reduced and during cyclical, apparently-controlled HBV replication off treatment. Upstream regulators associated with the activated canonical
pathways were IFNɣ and LPS, among others. Some of the same pathways were very modestly activated during high viral replication before and after treatment in HBeAg-positive chimps P-1 and P-2 and
HBeAg-seroconverted chimp S-2, all of which had high viral replication prior to and following RNAi treatment. In conclusion, one chimpanzee serocleared HBeAg on therapy and demonstrated persistent viral
control off therapy that resembled inactive carrier state as in the HBeAg-negative chimpanzees. The remaining chimps, while responsive to therapy, did not appear to have lasting immune changes and were
unable to demonstrate altered viral control upon therapy discontinuation.
|
|
发表于 2018-10-13 10:31
