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Sharp Believes miRNAs Could Make Effective Therapeutic Targets

BOSTON (GenomeWeb News) - The amount of research into using microRNAs therapeutically has been growing in recent years amid a growing body of data linking the small, non-coding RNAs to various disease states. Still, concerns persist over the possibility that modulating miRNA expression may have unintended effects since they are believed to regulate multiple targets.
But according to Massachusetts Institute of Technology researcher Phil Sharp, this doesn’t necessarily mean that miRNAs won’t prove to be good targets for therapeutic intervention.
Currently, as many as 1,000 miRNAs are believed to be encoded by the human genome. Since miRNAs don’t require perfect complementarity to their mRNA target to trigger inhibition, it has been estimated that they regulate as much as one-third of all genes.
“I think about microRNAs in much the same pattern that I think about transcription factors,” Sharp said during a presentation at the American Society of Gene Therapy meeting here this week. “Transcription factors are known to regulate a few genes critically. … But they interact with hundreds of genes … and we know they have overlapping patterns of expression.”
Despite this, “we’ve been able to use transcription factors for therapeutic targets for a long time,” he said. “All small steroid-based drugs are targeting estrogen receptors and progesterone receptors and others … and regulating genes in transitional states. So I think you could possibly think of microRNAs as [a therapeutic] target either by tuning them up or tuning them down.”
A number of different approaches are being explored to regulate miRNA expression, including the use of antisense-like agents such as antagomirs and locked nucleic acids, as well as miRNA sponges, which are essentially transcripts expressed from strong promoters that contain multiple tandem binding sites to an miRNA of interest.
Thus far, the antisense-type of approach has been one of the most popular in the field, and this week Danish biotech firm Santaris Pharma announced that it had begun a phase I study of an LNA-based drug that inhibits miRNA-122 as a treatment for hepatitis C, marking the first time an miRNA-targeting agent has been tested in humans.
Despite this milestone, the miRNA drug field faces many hurdles, primarily related to delivery.
Even if Santaris’ drug is successful, since it is designed to work in the liver, an organ to which oligonucleotide drugs can easily be delivered, it remains unclear whether miRNA drugs will be effective for diseases affecting other tissues.
“If you think about what’s been done over the last 10 years with antisense … the delivery issue has clearly been not solved,” Sharp said, and whether drugs that either up-regulate or down-regulate miRNAs will be forthcoming “is probably going to take a while to figure out.”

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