“Where there is no vision, the people perish.” –King Solomon, Proverbs
A recent study (NEJM 2013; 368: 1685-94) sheds light on a new vision of potential therapies, using microRNAs designed to interfere with the pathogenesis intracellularly. While this study used this technology to target the Hepatitis C virus (HCV), the same technology has already received FDA approval for a medication (mipomersen) used to treat familial hypercholesterolemia.
With familial hypercholesterolemia, antisense oligonucleotides were developed which inhibit the expression of apolipoprotein B-100 in the liver. For HCV, miravirsen is a 15-nucleotide antisense oligonucleotide microRNA (miR-122) which binds two highly conserved sites in HCV RNA. The liver-expressed miR-122 protects HCV from degradation. Thus, the antisense oligonucleotide miravirsen causes degradation of HCV. All strains of HCV depend on miR-122. (This aspect is reiterated in an associated editorial: NEJM 2013; 368: 1741-43.)
This study enrolled 36 patients from 2010 to 2011 in a randomized, double-blind, placebo-controlled, sequential series, ascending multiple dose-ranging study (7 study sites). All HCV patients had not received previous therapy and were genotype 1. Patients received five weekly subcutaneous injections of miravirsen at 3 mg/kg, 5 mg/kg, 7 mg/kg or placebo injections.
Results: In the miravirsen groups, the mean maximum log reduction in HCV RNA level was related to dose: 1.2 in 3 mg/kg cohort, 2.9 in 5 mg/kg cohort, and 3.0 in 7 mg/kg cohort compared with a 0.4 reduction in the placebo cohort. During 14 weeks of follow-up after completing treatment, HCV RNA was not detected in one patient in the 5 mg/kg group and in four patients in the 7 mg/kg group.
There were no dose-limiting toxic effects or treatment discontinuations because of adverse events. However, cholesterol levels did decrease by ~25%. No viral resistance was identified. In addition, during treatment with miravirsen, a sustained decrease in serum alanine aminotransferase was evident.
The authors note that the pharmacologic data from this study indicate that once-monthly regimen would be feasible. Because miravirsen is not a substrate for P-450, it is not expected to have significant drug-drug interactions. Further studies are underway.
Potential drawbacks of treatment: miR-122 is a tumor-suppressor gene for hepatocellular carcinoma (HCC). Thus, treatment with miravirsen could increase the risk of HCC. Also, in mice that lack miR-122, there is a high risk of fatty liver and fibrosis.
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