A project grant from the NC3Rs has enabled Professor David Baker, from Queen Mary, University of London, to refine the traditional mouse model used to study multiple sclerosis. The new model is less severe as it avoids the use of paralysis, and also utilises fewer animals.
Principal Investigator: David Baker, Professor of Neuroimmunology
Organisation: Queen Mary, University of London
Award: £368,512, in 2010, over 24 months
Title: A refined animal model of multiple sclerosis
Read more about Professor Baker's research
Multiple sclerosis is a highly debilitating autoimmune disease
Multiple sclerosis is an autoimmune neurodegenerative disease which affects the central nervous system. It is characterised by loss of the myelin sheath which surrounds the axons of neuronal cells in the brain and spinal cord and is essential for the rapid transmission of nerve impulses.
Multiple sclerosis is the most common neurological condition in young adults with approximately 100,000 people in the UK affected. Disease onset is usually between the ages of 20 to 40, with women twice as likely to develop it as men. The disease typically involves episodes of paralysis followed by remission, however, it is chronic and progressively worsens. Symptoms range from pain, tremor and incontinence through to visual disturbances, difficulties with movement and coordination, and cognitive problems.
Traditional animal models of multiple sclerosis involve substantial suffering
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that is widely used as a model of multiple sclerosis. It can be induced in a range of species from rodents to non-human primates by immunisation with myelin antigens. Studies of EAE in mice involve paralysis of the hindlimbs and sometimes forelimbs and, as such, are classified as causing substantial suffering under the Animals (Scientific Procedures) Act 1986. In a typical study, animals are killed at various time points to examine disease progression. This necessitates the use of large numbers of mice; eight to 25 per group depending on the experiment. Analysis requires detailed histology which is time consuming.
New treatments are required for the chronic phase of the disease
The EAE model shows several features of multiple sclerosis and has therefore been used extensively in research. It has also contributed to the development of new treatments. EAE models are, however, limited in that they represent acute central nervous system inflammation, whereas progression of multiple sclerosis has been shown to involve other mechanisms of neurodegeneration which are independent of the immune system. The latter phase of the disease is not well treated and there are few models available to study neuroprotection and repair.
A novel model to study nerve cell loss in multiple sclerosis
With NC3Rs funding, Professor David Baker, the Blizard Institute at Queen Mary, University of London, has developed a new mouse model of multiple sclerosis which uses fewer animals and avoids paralysis.
The model is based on optic neuritis which is typically an early symptom of multiple sclerosis in humans. Optic neuritis results in damage to the optic nerve and loss of retinal ganglion cells, which continues as the disease progresses. Two lines of transgenic mice have been crossed: one which has T cells which target a protein called myelin oligodendrocyte glycoprotein (leading to demyelination) and the other which expresses cyan fluorescent protein in the retinal ganglion cells. Levels of myelin oligodendrocyte glycoprotein are higher in the optic nerve than in the spinal cord and as a result the mice develop optic neuritis without EAE and the associated paralysis. Optic nerve damage can be tracked by following the expression of cyan fluorescent protein in the retinal ganglion cells. This provides a novel model which allows autoimmunity, neurodegeneration and neuroprotection to be studied and can be used to replace some use of the EAE model.
Paralysis is avoided and animal suffering is minimised
The mouse optic neuritis model, combined with the fluorescence tracking of nerve cell loss, has a number of advantages over the EAE approach. Paralysis is avoided and therefore there is less animal suffering. This procedure is classified as causing moderate suffering under the Animals (Scientific Procedures) Act 1986, rather than the substantial suffering associated with the EAE model. Although optic neuritis can impair vision, mice do not use sight as their primary sense and are able to cope well. Furthermore, the whole experiment can be performed in one to two weeks rather than the typical three to four weeks with the EAE model and therefore any suffering is further minimised.
Nerve loss in mice is monitored using the same technology as in patients
A further advantage is that optical damage can be monitored non-invasively using optical coherence tomography, a technique which is also used for measuring nerve loss in multiple sclerosis patients.
Optic damage can be monitored in the same animals for the duration of the study without the need to cull mice at different time points for histology.This me ans that the number of animals used can potentially be reduced compared to standard models. The imaging studies are currently being further optimised in order to maximise the benefits of the new mouse model.
A new clinical trial design for the treatment of multiple sclerosis
Based on the development of this refined model, Professor Baker has already secured funding from the Multiple Sclerosis Society of Great Britain and Northern Ireland and the UK Stem Cell Foundation to examine methods of neuronal repair. The model has also helped the development of a new clinical trial design for the treatment of multiple sclerosis in humans, with the first trial to start in 2011/12.
There has been one publication to date arising from this grant.
This case study was published in a review of our research portfolio in September 2011.