SPC3649: Targeting the Liver to Combat Hepatitis-C Virus

The hepatitis-C virus (HCV) is a bloodborne pathogen that infects approximately 170 million people worldwide (1). The virus infects the cells composing the liver known as hepatocytes and can cause hepatitis, cirrhosis, and liver cancer over time. Current therapies for HCV infection can cause debilitating side effects and are not always successful in controlling the virus. A new study published in the journal Science exploited the replication cycle of the virus to assess a novel drug in combating HCV (2).

The study was based upon previous work suggesting that HCV replication relies on a liver specific microRNA (miRNA) known as miR-122 (3). The authors used a locked nucleic acid modified phosphorothioate oligonucleotide, or more simply put, a specific inhibitor of miR-122 deemed SPC3649.

The authors treated HCV infected chimpanzees for 12 weeks with weekly intravenous infusions of SPC3649. After the 12 week treatment period, the chimpanzees were left untreated for an additional 17 weeks. Over the treated and untreated time periods, the authors tracked HCV RNA levels in the serum and liver, a marker indicative of viral replication.

With a 5 mg/kg dose of SPC3649, the authors observed an approximate 2.3 orders of magnitude reduction in liver HCV RNA during the 12 week treatment time. A decrease in serum HCV RNA was also observed. During the 17 week untreated period, HCV RNA levels slowly rebounded back towards that observed before SPC3649 treatment began. This suggests that the decline in HCV RNA during the treatment period was indeed SPC3649 specific.

Northern blot analysis for miR-122 levels demonstrated that SPC3649 was binding and forming a complex with its target, thereby inhibiting it. The SPC3649/miR-122 complex dissipated over the 17 week untreated time period, again demonstrating the specificity of the inhibitor. Moreover, liver sections from treated chimpanzees demonstrated histological improvement. This suggests that SPC3649 many not only inhibit HCV replication but also help heal damage to the liver.

Although the results presented in the study suggest that SPC3649 can control HCV in chimpanzees, its efficacy and safety will need to be assessed in human trials. Santaris Pharma is currently enrolling volunteers for a phase I study (ClinicalTrials.gov Identifier: NCT00979927) to assess the safety of the inhibitor in healthy individuals (4). SPC3649 may offer a new hope to HCV infected individuals outside of current available therapies.

References:

1. Perrault, M. and Pecheur, E. Biochem J. 2009. 423; 303-314

2. Lanford, RE. et al. Science. 2010. 327; 198

3. Jopling, CL. et al. Science. 2005. 309; 1577

4. ClinicalTrials.gov Identifier: NCT00979927. http://clinicaltrials.gov/ct2/show/NCT00979927. Accessed 1/26/2010