Treating strokes: New therapy in sight

Recurrent strokes in the days and weeks following the initial event are a common problem among patients in whom arteriosclerosis was the cause. An international team of researchers led by the LMU Hospital has now investigated in detail why these recurrent strokes occur: after the initial event, genetic material (DNA) released from cells leads to an inflammatory reaction throughout the body, which also leads to a worsening of the arteriosclerotic vascular deposits and thus to renewed vascular occlusions - a vicious circle. The research team led by Arthur Liesz, Professor at the Institute for Stroke and Dementia Research and member of the SyNergy Cluster of Excellence, is therefore proposing a new therapy based on its new findings: simply breaking down the cell-free DNA using appropriate drugs (DNases). The results of the study have now been published in the scientific journal Nature and, if confirmed in humans, could lead to improved stroke therapy.

Stroke due to stroke

Around 200,000 people in Germany suffer a stroke every year. This makes it the second most common cause of death - and a major cause of disability in adulthood. Strokes are usually caused by arteriosclerosis. This process occurs when immune cells migrate into fatty deposits in the blood vessel wall. A harmful inflammatory reaction builds up in the resulting “plaques”, which takes on a life of its own, becomes chronic, leads to calcifications and constrictions and clogs the vessels. What's more, clots can break free from these “plaques”, travel through the blood and block small vessels in the brain. However, why a good ten percent of patients suffer further strokes within days and weeks, even with the best care in hospital, remained unexplained for a long time.

“We have now largely solved this mystery,” says Arthur Liesz. The basis for this was initially the establishment of a so-called animal model in mice, in which the researchers were able to simulate recurrent strokes from arteriosclerotic plaques as in humans in order to investigate the processes involved.

Free DNA in the blood leads to inflammatory reactions

It turned out that in the early phase after a stroke, there is an inflammatory reaction throughout the body - even though there is no infection. The researchers were able to identify the cause as cell-free DNA in the blood that is actively secreted by so-called neutrophils, an innate immune cell type. It causes inflammation, which also causes arteriosclerosis to progress rapidly, because “this cell-free DNA activates the AIM2 inflammasome in certain immune cells,” says postdoctoral researcher Jiayu Cao. The inflammasome is a whole complex of proteins in inflammatory cells that leads to the massive production of the messenger substance interleukin-1. This messenger substance spreads through the blood throughout the body and has a particular effect on tissue that is already inflamed - such as arteriosclerotic vessels. This in turn destabilizes high-risk plaques, which rupture and release clots, leading to further strokes.

With this knowledge, the researchers started a therapy in their animals after the first stroke: by administering so-called DNases - enzymes that destroy DNA - immediately after the first stroke, the entire fatal process can be stopped. “With this treatment, we have reduced the rate of recurrent strokes in our animal model by up to 80 percent,” says postdoctoral researcher Stefan Roth. The DNA in cells remains unaffected by this treatment because DNases cannot penetrate cells. “The success in animal experiments has motivated us to plan a clinical trial, which has already been approved.” According to Liesz, it is “expected to start in 2025 at several clinics in Germany.”

Original work:

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