Blocking a unique type of cell death that occurs in multiple sclerosis could be a way to halt the debilitating disease, according to new research.
Pyroptosis, or “fiery death,” is the cell death process to which the new study refers.
It is also the “primary mechanism” behind the destruction of nerve-insulating myelin that occurs in multiple sclerosis (MS), say the researchers.
A paper now published in the Proceedings of the National Academy of Sciences reports how the scientists observed the process in an animal model of MS and in brain tissue from patients with the disease.
The study is the first to explain how pyroptosis works at the molecular level in the human brain.
“This could be a game changer,” explains senior study author Prof. Christopher Power, who is a co-director of the MS Center at the University of Alberta in Canada, “because we discovered a fundamental mechanism by which brain cells are damaged in MS that couples inflammation with neurodegeneration.”
He and his colleagues also found a way to block the enzyme that drives the mechanism with an experimental drug called VX-765 that is being tested for treating epilepsy. “The drug is already known to be safe in humans,” he adds.
MS is a lifelong, currently uncurable, disease that affects the central nervous system (CNS), which comprises the brain, the spinal cord, and the optic nerves that connect the eyes to the brain.
Many scientists now believe that MS is an autoimmune disease that can arise when the immune system mistakes healthy tissue as a threat and attacks it, causing inflammation and destruction of the healthy tissue. However, what triggers the immune system to behave in this way is still unclear.
In MS, the immune system attacks myelin, the protein sheath that surrounds and insulates the nerve fibers that carry signals to and from the CNS. These attacks can sometimes damage the nerve fibers themselves. The immune system also attacks oligodendrocytes, or the cells that make myelin in the CNS.
The result is a multiplicity of symptoms, depending on which parts of the CNS are affected, that vary unpredictably among individuals and also in the same individual over time.
Typical symptoms include but are not limited to: disturbed vision and sensation, mobility issues, numbness, speech difficulties, and immense fatigue.
Estimates suggest that there are more than 2.3 million people worldwide living with MS. However, there are no official figures for the United States because doctors do not need to report newly diagnosed cases.
However, a study presented at a conference in 2017 suggested that the U.S. may have nearly 1 million people with MS.
Scientists once thought that cell death was just an unavoidable, “spurious consequence of cellular life.”
However, mounting evidence over recent decades has revealed that — aside from “accidental cell death” — there are many forms of “regulated cell death.”
These genetically programmed processes prune excess cells and destroy those that might cause harm or are permanently damaged.
Experts are considering a new way of classifying cell death that takes more account of its molecular characteristics.
Pyroptosis, or fiery cell death, is one of these. It got its name from the fact that it is triggered by inflammation molecules, or “inflammasomes.”
In their study paper, Prof. Power and colleagues explain that researchers have recently identified that the main “executioner” of this type of inflammasome-driven cell death is a “pore-forming protein” called gasdermin D (GSDMD).
They also note that although it was known that the molecule caspase-1 can activate GSDMD, it was not clear whether “this process contributes to neuroinflammation.”
Their study provided “molecular evidence” that pyroptosis is the form of cell death that occurs in MS, and that it is activated by enzymes that trigger GSDMD.
The authors were surprised to find that pyroptosis occurred not only in “myeloid cells,” but also in “myelin-forming oligodendrocytes.” They observed this in tissue of the CNS of people with MS, as well as in an animal model of MS.
In further experiments, the researchers exposed both cell types to “inflammatory stimuli” and saw that they triggered “inflammasome activation and pyroptosis.”
Finally, the team showed that a small molecule called VX-765 inhibited caspase-1 and “prevented pyroptosis in experimental models of MS, reducing demyelination and neurodegeneration.”
“We think this drug,” says first study author Brienne A. McKenzie, who is a post-graduate student in Prof. Power’s laboratory, “would break the cycle of neurotoxic inflammation and thus prevent future loss of brain cell[s] in MS.”
The researchers suggest that their findings could also lead to new ways to monitor progress in MS, something that is currently very difficult to do as the symptoms are so varied and can change over time.
Commenting on the significance of the study, Dr. Avindra Nath — clinical director of the National Institute of Neurological Disorder and Stroke in Bethesda, MD — says that current treatments for MS aim to “reduce inflammation, but there is nothing that targets the brain cells themselves.”
“This paper identifies a clinically relevant novel pathway that opens the doors to new therapeutic targets that prevent cell damage.”
Dr. Avindra Nath