Treating strokes: new therapy on the horizon

Recurrent strokes in the days and weeks after the initial event are a common problem in patients for whom arteriosclerosis was the original cause. An international team of researchers under the aegis of LMU University Hospital has now carried out a detailed investigation into why recurrent strokes occur so often. They discovered that DNA released from cells after the initial event induces an inflammatory response in the entire body, which – among other things – leads to a deterioration of arteriosclerotic plaques and thus to new vascular obstructions – a vicious cycle. The research team, which is led by Arthur Liesz, Professor at the Institute for Stroke and Dementia Research and member of the SyNergy Cluster of Excellence, has proposed a new therapy based on its findings, which involves breaking down the cell-free DNA by means of suitable drugs (DNase enzymes). The study results have now been published in the scientific journal Nature. If confirmed in humans, the findings could lead to improved stroke therapy.

One stroke causing others

Around 200,000 people have a stroke in Germany each year. It is the second most common cause of death – and one of the main causes of disability in adults. A big proportion of strokes is usually caused by arteriosclerosis. This process occurs when immune cells migrate into fatty deposits in the walls of blood vessels. A harmful inflammatory response develops in the resulting plaques. This response develops its own momentum, becomes chronic, leads to calcification and constrictions, and clogs up the vessels. Moreover, blood clots can break away from these plaques, travel in the bloodstream, and block small vessels in the brain. But for a long time, scientists were at a loss to explain why some ten percent of patients suffered further strokes within days and weeks of the first one, even when given the best hospital care.

“We’ve now largely solved this mystery,” says Arthur Liesz. The foundation for this breakthrough was laid by establishing a mouse model, on which the researchers could reproduce recurrent strokes from arteriosclerotic plaques as they occur in humans in order to investigate the processes involved.

Free DNA in the blood leads to inflammatory responses

It transpired that in the early phase after a stroke, an inflammatory response occurs in the entire body – despite there being no infection. The researchers were able to identify the cause as cell-free DNA in the blood, which is released actively from neutrophils, an innate immune cell type. This induces an inflammation, which then causes the arteriosclerosis to rapidly progress. As postdoctoral researcher Jiayu Cao explains: “This cell-free DNA activates the AIM2 inflammasome in certain immune cells.” Inflammasome is the name given to a complex of proteins in inflammatory cells, which leads to mass production of Interleukin-1. Carried by the bloodstream, this signaling molecule spreads throughout the body and particularly affects tissue that is already inflamed – such as the vessels altered by arteriosclerosis. This in turn destabilizes high-risk plaques, which break down and release clots, leading to further strokes.

Armed with this knowledge, the researchers started a therapy on their animals after the first stroke. By administering so-called DNases – enzymes that destroy DNA – immediately after the first stroke, the whole fatal process can be arrested. “With this treatment, we reduced the rate of recurrent strokes in our animal model by up to 80 percent,” says postdoctoral researcher Stefan Roth. Because DNases cannot penetrate into cells, the DNA inside them remains unaffected by the treatment. “The success of the animal experiments has encouraged us to plan a clinical study, which has already been approved.” Liesz expects trials to begin at several clinics in Germany in 2025.

Jiayu Cao, Stefan Roth et al.: DNA-sensing inflammasomes cause recurrent atherosclerotic stroke. Nature 2024