microRNAs entice as diagnostic key to multiple diseases

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Anne Paxton

June 2014—In research and development of diagnostics based on the small, non-coding RNAs known as microRNA, the potential clinical applications in cancer were the first to be explored and have hogged the spotlight. But the more light that is shed on micro­RNAs’ mysteries, the more promise microRNA shows as a diagnostic and therapeutic tool in an array of diseases beyond cancer.

The numbers hint at the scope and magnitude of microRNAs’ possible roles. More than 1,000 microRNAs are predicted to exist in the human genome, with each one potentially targeting hundreds of messenger RNAs. Therapies using microRNA to suppress hepatitis C viruses are already in human trials, while basic research in not only liver disease but also diabetes, cardiovascular disease, and neurodegenerative diseases, among others, is laying the groundwork for many more clinical trials within the next five to 10 years.

“The cancer field is ahead of us. But microRNAs are not only important in cancer,” says Walter Lukiw, PhD, professor of neurology, neuroscience, and ophthalmology at the Louisiana State University Neuroscience Center. “MicroRNAs are ubiquitous and are proving to have huge effects in development, aging, and health and disease.”

Demonstration of this fact has led to a tremendous acceleration of micro­RNA research, says Eric N. Olson, PhD, professor and chair of molecular biology at the University of Texas Southwestern Medical Center in Dallas. A key research interest in his laboratory is the molecular basis of heart development and disease—studies of how the heart forms, functions, and dysfunctions. The laboratory chose to zero in on microRNAs when it became apparent that they were regulated in many types of disease processes and play a crucial role in cardiovascular disease. (Small EM, et al. Circulation. 2010;121:1022–1032.)

He finds microRNAs particularly fascinating as biomarkers of disease. “They are secreted from cells, they circulate in all bodily fluids including blood, and you can diagnose various disorders in the cardiovascular system by the presence of microRNAs in the bloodstream,” he says.

Dr. Olson describes microRNA as a kind of “dimmer switch” for cells. “They dial down gradually the expression of many different proteins in a cell, and it’s the combined, gentle effect of the microRNA across many different proteins that ultimately influences how the cell behaves in response to a disease.” The things that go awry in a cell that cause disease are controlled by microRNAs, he adds. “So if you can modulate the microRNA, you can modulate the disease.”

Dr. Olson

At his medical center, research has indicated that microRNAs are not merely involved in the cardiovascular disease process but are actually front and center, Dr. Olson says. “We identified a collection of microRNAs in rodents and humans that changed in abundance during the progression of heart disease. We made genetic deletions in mice and also over-expressed microRNA genes, which caused interesting disease phenotypes.” By manipulating the micro­RNAs, he explains, you can either diminish the symptoms of disease or worsen the disease. Based on that research, “we began to explore in more detail how microRNAs might modulate disease progression in the cardiovascular system.”

Dr. Olson is optimistic about potential therapeutic applications, and has already co-founded a biotechnology company called miRagen Therapeutics, which is working on developing new drugs to control microRNAs’ biology over a variety of diseases. The company is now conducting studies of human disease in large animal models and carrying out preliminary toxicology studies on drug compounds involving microRNAs.
He thinks heart failure, fibrosis, and vascular disorders due to excessive vascular growth are the main likely candidates for microRNA therapies in cardiovascular disease.

What would give microRNAs an edge over other drugs? “MicroRNAs are based on an entirely different mechanism of action,” Dr. Olson points out. “The classical drugs we’re all familiar with generally act against single proteins in cells, most often inhibiting a cell surface receptor or protein kinase. But cells have ways of bypassing the activity of a drug by removing the protein to which the drug is targeted.”

“MicroRNAs, instead of targeting one protein to maximally inhibit it, target a large collection of proteins across a complicated biological pathway, so bypass mechanisms are less likely.” However, the same feature makes it difficult or even impossible to correlate the therapeutic effect of a microRNA-based drug with inhibition of a protein or cell. “There are many other therapeutic modalities that can be brought to bear on cardiovascular disorders,” Dr. Olson adds. “MicroRNAs are but one of the modalities in the armamentarium.”

It was a 2008 paper, the first reporting on the use of plasma-based microRNAs to detect pancreatic cancer, that drew Sok Kean Khoo, PhD, to study possible applications to neurodegenerative disease. By applying what has been learned in oncology, she felt that researchers could help the understanding of neurodegenerative disease catch up to microRNA applications in cancer. “I think micro­RNAs are definitely relevant to all diseases; it’s just that we haven’t done enough research yet,” says Dr. Khoo, distinguished associate professor of molecular genomics at Grand Valley State University in Michigan.