Packard Scientists Identify a Small RNA Molecule that Contributes to ALS

Packard Investigator Tim Miller’s new study highlights a new potential therapeutic target for ALS.

Packard scientists may have identified a new potential therapeutic target for ALS. In a Human Molecular Genetics study that was published today, neurologist Timothy Miller at Washington University in St. Louis and colleagues showed that some small pieces of RNA known as microRNAs can affect ALS. In particular, Miller and colleagues showed that levels of a specific microRNA known as miR-155 could affect both disease progression and duration.

“We were able to show in a mouse model that the mice with inhibited miR-155 lived longer. That suggests that increased miR-155 is detrimental to the disease course. It may or may not be involved in the cause of disease, but it’s clearly contributing to the acceleration of disease because when we inhibit miR-155, we slow down the disease,” Miller said.

Previous studies indicated that microRNA function is altered in a variety of diseases, including cancer and autoimmune diseases like lupus. As well, research has shown that microRNAs are especially important in immune functioning. Given that immune system involvement is an important factor in ALS, Miller and colleagues thought that microRNAs might play a role in disease.

Erica Koval, a PhD student at Washington University, and lead author on the manuscript compared levels of nearly 700 microRNAs in the spinal cords of rodent models of ALS, ALS patients, and healthy controls. Of the 12 microRNAs with altered expression in mice, rats, and ALS patients, the researchers focused in on the molecule that had the highest and most significant dysregulation: miR-155. Levels of miR-155 were increased five-fold in mouse spinal cords and were two times higher in the spinal cords of ALS patients.

The researchers then treated ALS model mice with an anti-miR-155 compound from Regulus Pharmaceuticals, which was a short sequence of chemically synthesized DNA that would bind to miR-155 and inactivate it. At 60 days of age, the researchers began infusing ALS-model mice with the anti-miR-155 molecule. Miller and colleagues tracked the age, weight and progressive paralysis of these animals.

Administration of anti-miR-155 didn’t alter disease onset but it did improve disease survival and duration. These results are important, Miller says, because they provide a totally new class of potential therapeutic target for ALS, especially since miR-155 levels are also increased in sporadic ALS patients. And since miR-155 levels can be easily measured in a blood sample, researchers may one day be able to tailor these treatments to the right individuals. Before these therapeutics become available in humans, however, they still require further rodent testing and other pre-clinical experiments.