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Mar 15, 2010 (Vol. 30, No. 6)

miRNAs' Therapeutic Potential

Scientists Scrutinize Promising Molecules as Potential Drug Targets and Biomarkers

  • Cardiovascular Disease

    Click Image To Enlarge +
    Masson trichrome staining from sections of a nondiseased mouse heart (left) and a mouse heart 14 days after myocardial infarction (right) (miRagen Therapeutics)

    miRagen Therapeutics develops miRNA-based therapeutics for cardiovascular and muscle disease. William S. Marshall, Ph.D., miRagen’s president and CEO, will talk about identification of miRNAs associated with cardiovascular disease at the meeting. miRagen is developing miRNA inhibitors targeting miRNAs 15 and 208 to treat post-myocardial infarction remodeling and chronic heart failure, respectively. These miRNA targets were identified through extensive profiling efforts, and the company has performed validation experiments to show that these miRNAs control significant disease drivers thought to contribute to the development of pathological hypertrophy.

    The company recently showed that inhibition of miR-15, an miRNA that regulates several pathways implicated in the control of apoptosis, reduces the area of cardiac tissue death after a myocardial infarction. miRagen scientists have consistently observed upregulation of the miR-15 family (miR-195 and miR-16) in diseased versus normal heart tissue from multiple animal models and human samples, suggesting that upregulation of these miRNAs may inhibit the expression of pro-survival factors, thereby contributing to cardiomyocyte death.

    Subsequent studies have shown the benefits of inhibiting the targeted miRNA’s in rodent disease models. The company has demonstrated the benefits of antimiR-15 treatment after myocardial infarction in limiting the size of infarct, as well as reducing pathological hypertrophy in longer term studies. AntimiR-208 treatment in the transaortic banding model of hemodynamic overload showed a reduction in pathological hypertrophy, improvement of cardiac function, and inhibition in muscle form switch to the slower α-myosin form.

    Emerging reports suggest a potential role for miRNAs in both neuronal survival and the accumulation of toxic proteins associated with neurodegeneration, and how these proteins may themselves influence miRNA expression.

    Kai-Christian Sonntag, M.D., Ph.D., assistant professor of psychiatry at Harvard Medical School, will discuss studies under way to determine whether dysregulation of signaling pathways in Parkinson disease (PD) pathogenesis are associated with deregulated miRNAs. He and his colleagues, through miRNA profiling on laser-microdissected dopaminergic (DA) neurons from normal individuals and PD patients, found distinct miRNA expression patterns.

    According to Dr. Sonntag, “these studies showed dysregulation and, in particular, profound downregulation of gene expression relevant to PD pathogenesis. Additionally, using quantitative real-time (qRT)-PCR, we validated some of the microarray results and could confirm the observed downregulation of gene expression in PD. We also demonstrated that genes were differentially expressed within the DA neurons up to 200-fold, independent of gender or disease. Although this was consistent within the sample populations, we also observed high variation between individuals.”

    miRNA profiling was performed on the same sample population as the microarrays using laser microdissected DA neurons and high-throughput megaplex TaqMan® miRNA qRT-PCR assays (Applied Biosystems, part of Life Technologies) for 382 miRNAs including three conserved nuclear miRNAs.

    “Regardless of disease or gender we found that in all samples the SN DA neurons exhibited a distinct pattern (fingerprint) of miRNA expression. From the 379 miRNAs about 161 were expressed above detection threshold and the majority were higher expressed in PD.” However, Dr. Sonntag says, as in the microarrays, differences were often subtle.

    The scientists also did computational analysis to determine PD-specific miRNAs based on target predictions. “When we did negative correlations, we could identify about 20 miRNAs that had significant  target correlations. We then analyzed the pool of all targets for these 20 miRNAs using the same methodology as for the microarrays, for example, clustering the genes according to signaling pathways relevant to PD. This revealed that about 10 PD-specific miRNAs were prominent and four to six of them were overrepresented.”

    It appears that predicted targets for these miRNAs don’t seem to be key factors in PD. Rather the PD-specific miRNAs were associated with all signaling pathways related to PD such as growth factors, neurotransmitters, ion channels, protein degradation, synaptic dysfunction, and cytoskeleton, but surprisingly little mitochondrial dysfunction and programmed cell death. In addition, miRNAs seem to preferentially target members of gene subfamilies that are deregulated in our microarrays.”

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