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[Inhibitory effects of phosphorothioate antisense oligonucleotides on gene expression controlled by HCV 5'NCR in nude
1Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
Objective:
To evaluate the activity in vivo of 3 phosphorothioate antisense oligonucleotides, HCV363, HCV279 and HCV349 using nude mice xenograft models based on the establishment of HCV 5' NCR transgenic cellular model (HepG2.9706).
Methods:
Female BALB/C nude mice, aged 4 to 6 weeks and weighing around 20g, were implanted s.c. with 100mul (106 cells) of the HepG2.9706 cells suspension in the lower-back region. In approximate 1 weeks, the animals were randomly grouped and intraperitoneally administrated the antisense drugs at 10 mg/kg body weight.
Results:
HCV363, HCV279 and HCV349 had obvious sequence-specific inhibitory effects on luciferase expression controlled by HCV 5' NCR in xenograft cells with the inhibitory rates of 80.4%, 78.6% and 47.9%, respectively. The effects of three different concentrations (5, 10, 20 mg/kg body weight) of HCV363 indicated that HCV363 increased the inhibitory activities on luciferase expression following the concentration raise and its inhibitory rate was up to 82.7%.
Conclusions:
This study suggests that antisense oligonucleotides may provide a novel therapeutic approach to the treatment of HCV infection.
Insights
Three phosphorothioate antisense oligonucleotides demonstrated sequence-specific inhibition of Hepatitis C Virus (HCV) 5' NCR activity in vivo. HCV363 showed the highest efficacy, with inhibition rates up to 82.7%, suggesting a novel therapeutic strategy for HCV infection.
Area of Science:
- Hepatology and Viral Research
- Oligonucleotide Therapeutics
- Molecular Biology
Context:
- Hepatitis C Virus (HCV) infection remains a significant global health challenge.
- Developing novel antiviral strategies targeting HCV is crucial.
- Antisense oligonucleotides (ASOs) offer a promising avenue for sequence-specific gene silencing.
Purpose:
- To evaluate the in vivo efficacy of three phosphorothioate antisense oligonucleotides (HCV363, HCV279, HCV349).
- To assess the inhibitory activity against the HCV 5' NCR in a nude mice xenograft model.
- To determine the dose-dependent effect of the most potent ASO.
Summary:
- HCV363, HCV279, and HCV349 exhibited significant sequence-specific inhibition of luciferase expression driven by the HCV 5' NCR in xenograft models.
- Inhibitory rates were 80.4% for HCV363, 78.6% for HCV279, and 47.9% for HCV349.
- HCV363 demonstrated a dose-dependent effect, with increased concentrations (5-20 mg/kg) enhancing inhibition up to 82.7%.
Impact:
- These findings support antisense oligonucleotides as a potential novel therapeutic approach for treating HCV infection.
- The study highlights the potential of targeting the HCV 5' NCR for antiviral therapy.
- Further research into ASO-based therapies could lead to new treatment options for patients with Hepatitis C.
