VX-765 Therapy, Given Through Nose, Limits MS Progression in Early Study

The anti-inflammatory medication VX-765, which is delivered through the nose (intranasal), was found to limit disease progression in a preclinical model of multiple sclerosis (MS) by blocking a protein called caspase-1.

The medication helped prevent damage to brain cells in mice.

Researchers from the University of Alberta, in Canada, showed that injecting VX-765 — a known caspase-1 inhibitor — into the noses of the mice reduced signs of nerve cell degeneration seen in response to the protein’s activation.

The study, “Intranasal anti-caspase-1 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis,” was published in the journal GLIA.

Intranasal medications hold several advantages over other delivery methods, the researchers said.

“It’s a lot easier for patients because you need less of the drug. It’s a direct delivery into the brain, it doesn’t go into the circulatory system and it’s not broken down as quickly,” Christopher Power, MD, a neurologist and the study’s senior author, said in a university press release.

Caspase-1 has been eyed as a potential therapeutic target in MS based on evidence showing that it contributes to the loss of myelin — a hallmark of MS — and to nerve cell death.

Myelin insulates nerves like the plastic coating covering electrical wires. Without it, nerve signals are more easily disrupted, leading to common MS symptoms such as numbness and muscle spasms.

Applying a technique called RNA sequencing to brain slices from people both with and without multiple sclerosis, the researchers first showed that the gene for caspase-1, CASP1, was more active in normal-appearing white matter of MS. Normal-appearing white matter refers to brain tissue dense with nerve fibers that appears healthy despite being diseased at the microscopic level.

The researchers next cultured — grew in a lab dish — nerve cells from mice and treated them with a pro-inflammatory protein called TNF-alpha, which is known to be highly active in the central nervous systems of people with MS. The TNF-alpha treatment resulted in caspase-1 activation, reducing the activity of the gene for myelin (MBP), and leading to nerve death, the investigators found.

Building upon this observation, the team treated mice with a chemical called cuprizone, known to trigger demyelination, or the loss of myelin, and to mimic progressive MS in humans. As seen before, this appeared to induce caspase-1 activation and cause the loss of nerve cells.

However, when the researchers injected VX-765 into the noses of the mice, a reduction in the effects of all three events was seen. Specifically, caspase-1 induction, myelin loss, and nerve cell degeneration all were mitigated with intranasal VX-765 treatment.

Treatment with VX-765 also preserved the brain’s ability to take up the simple sugar glucose or glucose metabolism, an activity that is disrupted in the brains of MS patients.

“The current studies are the first demonstration that intranasal delivery of a caspase-1 inhibitor leads to improved outcomes in an established model of progressive MS,” the researchers wrote. “Furthermore, by blocking caspase-1 with VX-765, neuroinflammation … was reduced in the present model with concurrent protection of myelin and axons [nerve fibers].”

The researchers said having a therapy that’s easy to administer through the nose “represents an appealing opportunity to improve outcomes among people with progressive MS.”

Powerpositron emission tomography (PET) scanning, an imaging technique using radioactive substances to visualize changes in the body, helped the researchers to look at brain metabolism as part of the study.

“The study shows intranasal therapy is effective in preventing demyelination and axon injury and loss, so that’s a real tonic for us to keep going,” Power said. “The loss of myelin and loss of nerves are irreversible processes, so any therapeutic that helps to slow or prevent that from happening is an exciting advance for MS research.”