Microtargeting HCV

“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.

Related blog posts:

Working on biomarkers for Biliary Atresia

Two studies have tried to identify biomarkers to facilitate the diagnosis of biliary atresia (BA).

  • JPGN 2012; 55: 366-69
  • JPGN 2012; 55: 370-75

The first study looks at the serum of 24 patients with BA & 24 cholestatic controls.  Several circulating microRNAs (miRNAs) were associated with BA.  The miR-200b/429 cluster could correctly classify up to 85% of patients.

The second study took serum samples from 42 infants with BA, 38 infants with non-BA cholestasis, and 36 healthy controls.  Using mass spectrometry and enzyme-linked immunosorbent assays, they identified a candidate biomarker, Apo C-II, which was down-regulated in BA samples compared to healthy controls, but relatively upregulated compared with cholestatic non-BA samples.  The sensitivity of this model was 94% and the specificity was 92%.

Given the consequence of a missed diagnosis of BA, further work to identify biomarkers with even better sensitivity/specificity will be necessary to change current diagnostic algorithms.

Previous related blog entries:

MicroRNA signature for eosinophilic esophagitis

In a previous post discussing MicroRNAs (miRNAs) (MicroRNAs and biliary atresia), I stated that “Despite this intriguing research, it not clear whether or when miRNAs will have an important role in bedside management.”  Well, as more articles emerge on miRNAs, it is becoming clear that miRNAs will have a role in clinical medicine; the questions are when and what cost.

The latest study (J Allergy Clin Immunol 2012; 129: 1064-75) by Lu et al from Cincinnati shows how this technique can identify a specific signature for eosinophilic esophagitis (EoE) and how miRNAs can serve as a biomarker for disease response.  The investigators took plasma and esophageal biopsy specimens from patients with EoE, reflux esophagitis, and healthy controls; they used an array comprising 677 miRNAs.  254 miRNAs were expressed at greater than background levels, but 21 upregulated miRNAs and 11 downregulated miRNAs were markedly different.

To quickly understand how useful this technology could become requires a glance at the “heat maps” showing the expression profile of the 21 upregulated miRNAs and the 11 downregulated miRNAs, comparing EoE with healthy controls (Figures 1 & 3).  In addition, in Figure 3, it is readily apparent that the expression pattern is completely different from reflux esophagitis.  Furthermore, this figure demonstrates visually a normal-appearing pattern in patients who respond to fluticasone.

Other figures in the article and in the appendix demonstrate the complex relationships between these specific miRNAs and target genes.

Key points:

  • miRNAs from tissue or blood could serve as biomarkers for the presence of EoE and response to therapy
  • Of the identified miRNAs, miR-21 and miR-223 strongly correlate with esophageal eosinophilia as well as previously described EoE transcriptome
  • Plasma miRNAs that are most differentiated in EoE include miR-146a, miR-146b, and miR-223.

Related posts:

Guidelines for Eosinophilic Esophagitis

Eosinophilic Esophagitis -Six Food Group Diet

The undiscovered country

MicroRNAs and biliary atresia

The human genome may encode over 1000 microRNAs (miRNAs), which may target about 60% of mammalian genes and are abundant in many human cell types. MicroRNAs are a class of short (18-23 nucleotide) noncoding RNA molecules which act as a negative regulator of target mRNA stability and translation.  This month the interaction of miRNAs with biliary atresia is examined (JPGN 2012; 54: 186-92).

Using a mouse model, the authors identify miRNA-29 overexpression associated with the downregulation of two mRNA targets related to biliary atresia pathogenesis.  The research has several limitations, including the use of adult mice.  The reason why I highlight this study is that miRNAs are helping elucidate basic disease mechanisms and identifying new therapeutic targets.  Some of these same investigators published “Circulating microRNA is a biomarker of pediatric Crohn disease.” (JPGN: 2011;  53(1): 26-33).  In this study, 11 CD-associated serum miRNA were identified with encouraging diagnostic potential.  These specific miRNAs were found in Crohn disease patients but not in controls and patients with celiac disease.  The sensitivity for Crohn disease was over 80%.

Despite this intriguing research, it not clear whether or when miRNAs will have an important role in bedside management.

Additional references: