Renovo Neural Inc: repeated demyelination
New mouse model of repeated demyelination that results in a progressive neurological decline
Principal Investigator: Robin Avila, Ph.D
Institution: Renovo Neural, Inc.
Amount Awarded: €75,000
Multiple sclerosis involves repeated immune system attacks on the brain and spinal cord. Most people begin with a relapsing-remitting disease course of MS, which eventually develops into a progressive neurological disease course called secondary-progressive MS. Most treatments are approved for the people who are still experiencing relapses. One of the obstacles to developing treatments is the lack of animal models that mimic non-relapsing secondary-progressive MS. The purpose of this proposal is to develop a mouse model that will serve as a platform for testing new experimental strategies for stopping MS progression. The investigators propose to replicate some of the repeated injury that occurs over time and determine and document the longer-term consequences of that injury.
What does this mean for people living with progressive MS?
Developing a model for testing whether therapies can stop MS progression is a critical step in bringing these strategies from the laboratory to the clinic where they can end progression in people with MS.
Because no animal models currently exist to study the irreversible neurological decline seen in progressive MS, this project aimed to develop a model of progressive MS by inducing multiple cycles of demyelination in mice. It focused on three aspects of progressive MS; motor deficits, fatigue, and brain atrophy. The researchers used cuprizone (a chemical that induces myelin damage) to mimic several features of relapsing-remitting MS.
They theorized that repeated episodes of demyelination will create an environment in the brains of the mice that causes a late onset of axonal degeneration (nerve cell damage) and continuous neurological decline.
Eight- week-old mice were placed on a diet of cuprizone and received daily injections of rapamycin (a drug which suppresses the immune system) to induce demyelination. They received one, two, or three cycles of six weeks on this diet and six weeks on a normal diet. The control mice (that received no cuprizone) and those that received three cycles of cuprizone were monitored for changes in body weight, and evaluated for motor, sensory and cognitive deficits.
There was a significant decrease in the body weight of those that received three cycles. These mice also showed significant decrease in their front limb grip strength 77 weeks after the start of cuprizone but not at 62 weeks, demonstrating a progressive decline. There was a significant decrease in motor function in mice that received three cycles of cuprizone at 62 and 77 weeks.
To try to find a correlation between changes in the brain and progressive neurological decline, the researchers looked at demyelination and loss of axons (the long thread-like part of a nerve cell along which impulses are conducted from the cell body to other cells) in different cell types and brain regions.
When compared to the mice that had not received treatment, researchers found that the corpus callosum (the band of nerve fibres joining the two halves of the brain) in the mice that received three cycles of cuprizone had 70% reduction in corpus callosum thickness (significant white matter atrophy), 20% decrease in density of myelinated axons and 20% decrease in the density of oligodendrocytes.
This should provide a robust platform for investigating treatments that delay irreversible neurological decline in progressive MS.
Principal Investigator: Robin Avila
Robin Avila, PhD, earned her BS from the University of Vermont and her PhD in Biology/Structural Biochemistry from Boston College, where she studied myelin structural defects in rodent models of MS using X-ray diffraction. She completed her postdoctoral training focusing on gene regulation of the growth and specialization of myelin-making cells (oligodendrocytes) and myelination at University of Chicago. Dr. Avila now conducts research at Renovo Neural Inc. focusing on the development of pre-clinical models of multiple sclerosis.
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