2Rs (refining and reducing) of animal models of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune-mediated, neurodegenerative disease of the central nervous system (CNS), where about 80% of people will be severely disabled within 25 years of diagnosis. Whilst some progress has been made in the treatment of relapsing disease, there are no treatments that control progressive neurodegeneration in MS. The chief animal model of MS is experimental autoimmune encephalomyelitis (EAE) in rodents and primates, which if used appropriately can recapitulate many of the features of MS. These features are not adequately modelled in vitro, such that animal models cannot be "replaced" but models can be "refined" that will facilitate a "reduction" in animal use. Whilst EAE, is typically used to detect immune-influences there is an increasing need to detect neuroprotective effects. Disease in rodent EAE models results in periods of, subjectively-assessed, paralysis and the accumulation of neurological disability that often requires time-consuming, histology to assess. We aim to generate a model of MS, with reduced severity that can be used to assess neuroprotection and repair in wildtype and knockout C57BL/6 (EAE-low responder strain) animals. The visual system is commonly affected in MS and optic neuritis is typical early feature of MS. This results in visual impairment that is reflected by optic nerve damage and retinal ganglion cell (RGC) loss. This occurs in MS even in the absence of optic neuritis. The visual system is the most accessible neural pathway of the human CNS, and this has been proposed to be an important target lesion for repair and neuroprotection studies in MS. However, the optic nerve is not always affected during EAE. We will produce mice that express transgenes coding for myelin specific-T cell receptors and cyan fluorescent protein expressed in the RGC. These mice spontaneously, or can be induced without the need for Freund's adjuvant, to develop CNS autoimmunity in the optic nerve, in the absence of paralytic EAE, thus reducing the number of animals in substantial protocols. Damage in the optic nerve will be reflected by demyelination and loss of RGC that can be serially and rapidly quantitated using confocal scanning laser ophthalmoscopy and optical coherence tomography in the living animal. This when coupled with electrophysiology to detect demyelination and repair, can replicate proposed clinical studies and this will provide a valuable tool to detect, immunomodulatory, neuroprotective and repair agents that will reduce the number of substantial procedures and reduce the animals required to detect therapeutic effects.

Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Edith Chan AW, Amor S, Perkins V, Gerritsen WH,Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D (2014). Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain 137(Pt 1): 92-108 doi: 10.1093/brain/awt324

Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AW, Riddall D, Garthwaite J, Baker D, Selwood DL (2014) Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis.  Journal of Medicinal Chemistry 57(7): 2942-52 doi:10.1021/jm401881q

Lidster K, Jackson SJ, Ahmed Z, Munro P, Coffey P, Giovannoni G, Baker MD, Baker D (2013). Neuroprotection in a novel mouse model of multiple sclerosis. PLoS ONE 8(11): e79188 doi: 10.1371/journal.pone.0079188

Al-Izki S, Pryce G, O'Neill JK, Butter C, Giovannoni G, Amor S, Baker D (2012). Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. Mult Scler Relat Disord. 1(1): 29-38 doi: 10.1016/j.msard.2011.09.001

Lidster K, Baker D (2012). Optical coherence tomography detection of neurodegeneration in multiple sclerosis. CNS Neurol Disord Drug Targets 11(5): 518-27 doi: 10.2174/187152712801661185

Baker D, Gerritsen W, Rundle J and Amor S (2011). Critical appraisal of animal models of multiple sclerosis. Multiple Sclerosis Journal 17(6): 647-57 doi: 10.1177/1352458511398885

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Project grant

Status:

Closed

Principal investigator

Professor David Baker

Institution

Queen Mary University of London

Co-Investigator

Dr Mark Baker

Grant reference number

G1000094/1

Award date:

Oct 2010 - Sep 2012

Grant amount

£368,501