2Rs (Refining & reducing) of Animal Models of Multiple Sclerosis

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Multiple sclerosis (MS) is an autoimmune disease of the brain and spinal cord that results in nerve-damage and the accumulation of disability. Whilst some progress has been made in the treatment of relapsing disease, there are no treatments that control accumulation of progressive-disability. We aim to find useful treatments for this aspect of disease. The main animal-model of MS, used to assess the action of drugs prior to trials in humans, is an induced paralytic-disease called experimental autoimmune encephalomyelitis (EAE). Although we are not yet in a position to completely ?replace? animal use for identifying drugs to treat disease we can make these models better such that they can still detect drugs that stop the destructive actions of the white blood cells that drive nerve damage whilst limiting the suffering to the animals. This can be done by controlling the severity of disease and the length of time in procedure required to detect drug-effects. The optic nerve that links the eye to the brain is often damaged in MS and the visual pathway has been selected as an important system for testing new drugs for MS. Mice, do not use sight as a major sense and tolerate loss of vision. We plan to develop a mouse system that models this optic nerve damage, using genetically-engineered mice, whose white blood cells are programmed to attack only the optic nerve, whilst leaving the rest of the nervous system unaffected. Therefore, paralysis no longer develops and thus limits the suffering of animals. Furthermore, cells in the retina at the back of the eye will be made to glow, due to further genetic-engineering, following observation with a special-type of microscope through the eye. As optic nerves are damaged their glowing, cell-bodies are lost, thus the survival and death of nerves can be easily monitored in the living animal. This generates a significant improvement over existing models, where detection of nerve content is time consuming and requires test-animals to be culled at each observation point. As this new model can be serially-monitored, fewer animals will need to be used in experiments. Furthermore we can monitor nerve impulse transmission of the optic nerve, so that we can serially detect damage and repair for the first time. This provides a number of advantages over existing models and thus may encourage others to replace the existing severe model with the milder system to be developed in this project.