By Doug Macron
Though microRNAs hold great promise as diagnostic and prognostic biomarkers for a variety of complex diseases, their development for these applications outside of cancer remains years away, a Pfizer researcher said this week.
Indeed, cancer researchers have been a major force driving clinical applications of miRNAs, with at least four diagnostics based on the non-coding RNAs already commercialized.
To David von Schack, senior principal scientist of translational immunology in Pfizer's immunology and autoimmunity research unit, this makes sense given the fairly straightforward process of linking miRNAs to malignancies.
In oncology, “you know what your disease tissue is, you know what the cancer is, [and specimens] are typically abundantly available [since] people are more than willing to give up their cancer samples,” he said. But when working in other diseases — neurological conditions such as schizophrenia, for instance — it becomes a challenge even to obtain patient samples for analysis.
“It's a much more straightforward [path] to go from microRNA identification, then molecular understanding, and even applying [miRNAs in a clinical setting when] you can have access to tissue, versus other diseases where you just don't have access to the [implicated] tissue,” von Schack said.
In such cases, “you resort to secondary tissues as a readout, such as blood or other fluids, [but] then you're typically quite far removed from the source of action of the disease.”
At the same time, the molecular processes driving malignancy have been well studied and elucidated, von Schack noted on the sidelines of Cambridge Healthtech Institute's microRNA in Human Disease and Development conference in Cambridge, Mass., this week.
“That is much less understood in other diseases,” particularly autoimmune disorders, where “we know some of the affected organs and some of the cellular components, but the molecular machinery that leads to a certain disease's status” is not clear.
Yet von Schack sees great potential in the use of miRNA biomarkers in diseases beyond oncology, as evidenced by a research project he conducted while at Wyeth, which was acquired by Pfizer in 2009.
At the CHI meeting, von Schack presented data from that work, which appeared last year in PLoS One and showed that miRNAs may play a direct role in neuropathic pain.
The Wyeth investigators performed miRNA expression profiling in rats subjected to spinal nerve ligation. They found 63 miRNAs whose level of expression was “significantly altered” following the ligation surgery, including 59 that were down-regulated.
A computational prediction tool was used to identify the miRNAs' targets and “it was found that the transcripts with multiple predicted target sites belong to neurologically important pathways,” including ones involved in neurite growth, the Wyeth team wrote.
During his presentation, von Schack said that he and his colleagues hypothesized that many of the miRNAs identified may be expressed in order to inhibit early developmental processes, and that the damage caused by the spinal ligation led to their down-regulation as part of the regeneration process.
Still, the findings are very preliminary and “additional studies in neuropathic pain validating the role of individual miRNAs, employing both cellular and in vivo miRNA delivery … [are required to] elucidate the functional roles for these miRNAs in pain,” Schack and his team wrote in PLoS One.
Although the miRNA program was not continued after the rat study, Schack said that Pfizer is keeping its eye on the small, non-coding RNAs.
“We're interested. We're following the field,” he said. “To understand other facets of basic biology, you have to factor in microRNAs. ... You can't ignore them.
“But we're cautious [about] being at the forefront for [the sake of] being at the forefront. We want to have something that's biologically interpretable and useful in the clinic.”
That will likely mean taking cues from the cancer field, which has made great strides translating miRNAs into useful biomarkers.
Already, Rosetta Genomics has three miRNA-based cancer diagnostics on the market, and Asuragen recently introduced a fine needle aspirate version of its miRNA-based pancreatic cancer diagnostic (GSN 2/23/2012).
Exiqon, meanwhile, said earlier this month that it could have three miRNA cancer diagnostics, including one that uses biofluids rather than a tissue sample, on the market by 2014 (GSN 3/8/2012).
“As in so many other areas, cancer is going to lead the way,” von Schack said, although he cautioned that he views miRNA research in other disease areas trailing by five to ten years.
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