Promising New Stroke Therapy Comes from Inhibition of miR-155:
Imagine a treatment preventing further cell death in the brain following a stroke. Then throw in some anti-cancer and anti-inflammatory effects as an added bonus.
Sound too good to be true?
Dr. Tamara Roitbak from the Department of Neurosurgery at the University of New Mexico Health Sciences Center and her team of international colleagues have done just that. In her new study published in The Journal of Neuroscience, Roitbak demonstrated improved brain tissue recovery and motor behavior in mice by inhibiting a small molecule known as miRNA-155.
Previous research shows that inhibiting miRNA-155 reduces inflammation, accelerates wound healing, and might even have anti-cancer properties. Such a wide-range of effects are possible because miRNA-155 itself regulates the production of proteins involved in these processes.
Specifically, miRNA-155 is a molecule known as a microRNA. These microRNAs are responsible for inhibiting molecules known as messenger RNA, or mRNA, inside the cell. DNA is transcribed into this mRNA, which is then translated into proteins. So by inhibiting miRNA-155, proteins are freely produced that result in the regeneration of the brain vasculature following a stroke.
Roitbak’s team did not actually make the miRNA-155 inhibitor themselves. It was simply purchased from the biotech company Exiqon. But her study was the first to demonstrate that intravenous injection of a microRNA inhibitor can promote recovery following ischemic stroke.
Normal ischemic stroke treatment options include breaking up the blood clot or removing it mechanically. By contrast, Roitbak says her work aims to “respect the unique capacity of the brain to regenerate and avoid drastic intervention.”
“You don’t want to do a craniotomy on a stroke patient. So we are doing something that would be appropriate for a clinical study.”
For treatments aiming to break up the clot, she says that “tissue plasminogen activator (tPA) needs to be injected within 3 hours. But most patients come after that. So it is a real problem.”
“Additionally, very often these injections induce worse outcomes because tPA induces bleeding which can cause hemorrhagic stroke.” Stroke therapy is fraught with problems indeed. Not only does Dr. Roitbak’s new treatment avoid the bleeding potential of tPA, it also allows a more flexible timeframe of treatment since the first dose is not injected until 48 hours following the stroke.
The acute phase of inflammation accompanying a stroke is a volatile period for the brain that might be best left alone. “This acute inflammation can be neuroprotective due to glia cells that help promote regeneration,” which is why she waits 48 hours for the subacute phase to begin before the first injection of the miR-155 inhibitor.
There is minor caveat however. “The infarct itself cannot be rescued,” Roitbak explained, where the infarct is the site of dead brain tissue resulting from loss of blood supply. “But the area around it, the peri-infarct area, is the area that everybody is trying to rescue. Because if it is not helped it will become infarcted too.”
The results were clear that the miR-155 worked. More clear than she expected.
“When I looked at this area with the electron microscope it was very interesting to see how the microvessel, especially the tight junctions, were preserved compared to the control. It was surprising to see dead neurons in this area in control but no dead neurons in the peri-infarct area of the inhibited animal.”
“Also, what I like about the miRNA target is that they are fine tuners of protein expression. So we downregulated it only by 50% over 7 days,” Roitbak says. “You cannot make drastic changes. You have no right to. What I like is that we are doing very temporal fine tuning of the miRNA expression with minimal side effects.”
Based on previously published studies, Roitbak thinks it is likely the administration of miR-155 inhibitors in appropriate doses will only have positive side effects.
“The inhibitor not only goes into the brain, but everywhere. And miR-155 is also pro-carcinogenic. So we think that the total effect of the inhibition of miR-155 will only have a positive effect. We are also checking kidney and heart to look for changes, but we don’t expect anything negative.”
When asked about potential difficulties in moving this therapy into clinical trials, her initial concerns were financial rather than technical.
“First off, a challenge will be the price. The inhibitors are very, very expensive. So hopefully in the future they will become cheaper, because when you think about the clinical application of course you have to think about the price.”
“What you do in mice, especially in stroke research, doesn’t always work in humans,” she concedes. This is a concern for all of biomedical research, but apparently a particularly difficult problem for the stroke research studies.
“Nobody knows why they don’t translate from mouse to human in stroke. But I am very optimistic about this field of research.”
Phone Interview with Dr. Tamara Roitbak, on Monday, Sept. 14, 2015
“In vivo inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke.” Ernestro Caballero-Garrido, et al. Journal of Neuroscience, Sept. 9, 2015. 35(36):12446-1246