VX-765 Therapy, Given Through Nose, Limits MS Progression in Early… – Multiple Sclerosis News Today

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 proteins activation.

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

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

Its a lot easier for patients because you need less of the drug. Its a direct delivery into the brain, it doesnt go into the circulatory system and its not broken down as quickly, Christopher Power, MD, a neurologist and the studys 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.

Nerves in the brain are like insulated wires, but in MS there is initially a loss of the insulation [called myelin], and then the eventual loss of the wire, Power said. Those losses are caused by inflammation. That inflammation, which we think is the driving force for MS, is our main research interest.

According to the team, previous studies suggested that blocking caspase-1 resulted in improved outcomes in different MS models.

Since VX-765 is a caspase-1 inhibitor, the researchers hypothesized that it could be a therapeutic candidate for MS.

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 brains 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 thats easy to administer through the nose represents an appealing opportunity to improve outcomesamong 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 thats 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.

Forest Ray received his PhD in systems biology from Columbia University, where he developed tools to match drug side effects to other diseases. He has since worked as a journalist and science writer, covering topics from rare diseases to the intersection between environmental science and social justice. He currently lives in Long Beach, California.

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Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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