Researchers in the UK and Portugal report a novel therapeutic method that harnesses the body’s immune system to protect against brain damage following brain injury or stroke and in patients suffering from multiple sclerosis.
Traumatic brain injury is a significant cause of death worldwide and for survivors can cause long-lasting cognitive impairment and dementia. A leading cause of this cognitive impairment is the inflammatory response to the injury, with swelling of the brain causing permanent damage. While inflammation in other parts of the body can be addressed therapeutically, the blood-brain barrier prevents common anti-inflammatory molecules from getting to the site of trauma.
Led by Adrian Liston, a senior group leader in the Babraham Institute’s Immunology program, and Matthew Holt, Professor at VIB-KU Leuven Center for Brain & Disease Research, the authors describe a targeted delivery system that boosts the numbers of specialized, anti-inflammatory immune cells within the brain.
“Our bodies have their own anti-inflammatory response, regulatory T cells, which have the ability to sense inflammation and produce a cocktail of natural anti-inflammatories,” says Liston. “Unfortunately there are very few of these regulatory T cells in the brain, so they are overwhelmed by the inflammation following an injury. We sought to design a new therapeutic to boost the population of regulatory T cells in the brain, so that they could manage inflammation and reduce the damage caused by traumatic injury.”
In a recent issue of Nature Immunology, the research team describes finding few regulatory T cells in the brain because of a limited supply of the crucial survival molecule interleukin 2 (IL2). Levels of IL2 are low in the brain compared to the rest of the body as it can’t pass the blood-brain barrier. The team devised a new therapeutic approach that allows more IL2 to be made by brain cells, thereby creating the conditions needed by regulatory T cells to survive. The method involved a gene delivery system based on an engineered adeno-associated viral vector (AAV). Such a system can cross an intact blood brain barrier and deliver the DNA needed for the brain to produce more IL2.
”For years, the blood-brain barrier has seemed like an insurmountable hurdle to the efficient delivery of biologics to the brain,” Holt says. “Our work, using the latest in viral vector technology, proves that this is no longer the case; in fact, it is possible that under certain circumstances, the blood-brain barrier may actually prove to be therapeutically beneficial, serving to prevent ‘leak’ of therapeutics into the rest of the body.”
To test the efficacy of the treatment in a mouse model that closely resembles traumatic brain injury accidents, mice were given carefully controlled brain impacts and then treated with the IL-2 gene delivery system. The scientists found that the treatment was effective at reducing the amount of brain damage following the injury, assessed by comparing both the loss of brain tissue and the ability of the mice to perform in cognitive tests.
“Seeing the brains of the mice after the first experiment was a ‘eureka moment’ – we could immediately see that the treatment reduced the size of the injury lesion,” says lead author, Dr Lidia Yshii, Associate Professor at KU Leuven.
Recognizing the wider potential of a drug capable of controlling brain inflammation, the researchers also tested the effectiveness of the approach in experimental mouse models of multiple sclerosis and stroke. In the model of multiple sclerosis, treating mice during the early symptoms prevented severe paralysis and allowed the mice to recover faster. In a model of stroke, mice treated with the IL2 gene delivery system after a primary stroke were partially protected from secondary strokes occurring two weeks later. In a follow-up study, still undergoing peer review, the research team also demonstrated that the treatment was effective at preventing cognitive decline in ageing mice.
“By understanding and manipulating the immune response in the brain, we were able to develop a gene delivery system for IL2 as a potential treatment for neuroinflammation,” says Liston. “With tens of millions of people affected every year, and few treatment options, this has real potential to help people in need. We hope that this system will soon enter clinical trials, essential to test whether the treatment also works in patients.”