Fibrin, a protein that accumulates in the brain in MS, is the target for a new experimental therapy that aims to reduce damage to the brain. A treatment that suppressed fibrin was able to reduce inflammation and damage in the brain in laboratory models of MS.
Fibrin is a protein most well-known for its important role in blood clotting. When the body is wounded and starts to bleed, fibrin forms a mesh over the wound site to stop the bleeding. However, fibrin also builds up in the brain during some diseases such as MS and Alzheimer’s disease and the build-up of fibrin is thought to play a role in triggering the immune cell attack in the brain.
MS results from the immune cells attacking the coating around nerve fibres, known as myelin. In relapsing forms of MS, myelin is repaired by the body, leading to the typical symptoms of MS and subsequent recovery. But this process is often incomplete leaving the nerve fibres themselves exposed to further damage. This ultimately results in the accumulation of disability seen in the progressive forms of MS.
Current treatments for MS only act to stop the immune attacks but cannot repair this nerve damage. In a new study published in the prestigious journal Nature Immunology, researchers discovered that fibrin is in fact a trigger for the immune system to attack the brain via a particular biological pathway in diseases such as MS and leads to irreversible damage to nerves.
A treatment that targets fibrin and blocks its action would then seem to be an ideal solution but would require some careful thinking – treatments that affect fibrin throughout the body would result in dangerous disruptions to the body’s blood clotting processes. The trick would be to find a way to target the fibrin in the brain without touching the fibrin involved in wound healing.
And in this study, for the first time, researchers have found a way to do just that. They discovered that a particular part of the fibrin protein was exposed when it was interacting with the immune cells in the brain, and crucially, that this was different to the part that is exposed during the blood clotting process. They then screened potential drug molecules to identify one which blocks fibrin in the brain but doesn’t block blood clotting.
They showed that adding this molecule to immune cells and nerve cells together in a laboratory dish prevented the immune cells from damaging and killing the nerve cells. Using three separate laboratory models of MS, the researchers also showed that treating with the molecule before symptoms began delayed the onset of MS and reduced the symptoms. Treatment also stopped the immune cell attack on the nerve fibres in the spinal cord reducing damage, loss of myelin and inflammation. There was no effect on blood clotting and no effect on the immune system that is needed to fight infections in the rest of the body. In a parallel series of experiments, they showed that this molecule also prevents damage to the brain by immune cells in laboratory models of Alzheimer’s disease.
This work is very exciting as it reveals an entirely new way to potentially protect nerve cells in the brain and spinal cord. What is needed now is confirmation that this will also work in humans and then testing in clinical trials.
Fibrin accumulation is also a feature of other diseases that do not involve the brain, including rheumatoid arthritis, colitis and Duchenne muscular dystrophy, so important future work will need to look at whether these findings also apply to these other diseases. Treatments that aim to prevent damage within the brain and spinal cord are a huge unmet need in progressive MS and one of the key objectives of the International Progressive MS Alliance.
While still the early stages, findings such as these bring hope that treatments to prevent ongoing damage in MS will one day be a reality.