There is an urgent need for new treatment options to halt the disabling progression of multiple sclerosis (MS). Professor David Baker, Queen Mary University of London, explains how a novel animal model developed with NC3Rs funding offers a significant refinement improvement over previous animal models of autoimmunity, describing how it can be used to discover new treatments for people with MS.
I’m proud of many areas where Britain leads the world – sport (well, sometimes), culture (definitely) and the UK’s commitment to the ethical use of animals in research. Unfortunately, there is one claim to fame that we could well do without, this is being the global number one for the prevalence of MS. MS is the most common cause of neurological disability in young adults, affecting up to one in 350 people in some areas of the United Kingdom.
There is currently is no cure for MS, the slow progressive accumulation of disability continues unabated in sufferers, despite success in controlling some aspects of the disease. Whilst life-expectancy may not be curtailed too much, the quality-of-life for the people with MS and their carers deteriorates significantly, making it one of the few diseases where the advanced form is perceived as a fate worse than death.
Our lab group regularly engage and meet people with MS, which helps to motivate us to do something positive for those afflicted with the condition. Part of our quest is to understand the disease mechanisms and seek new treatment options.
Research using alternative methods to animals has so far been successful in mimicking some aspects of the disease. For example, an in vitro assay has been used to identify a molecular signalling pathway which resulted in the development of potent immunomodulatory drugs such as Tysabri (Natalizumab) to control relapsing MS. Despite this progress, work in animal models of the disease continues to play an important role in the development and regulatory approval of drugs. Animal models recapitulate many features of MS that cannot be modelled adequately in vitro, meaning that while animal models can’t be replaced they can be refined to reduce suffering.
The traditional animal model of MS is known as experimental autoimmune encephalomyelitis (EAE), this is the most common model of autoimmunity and is used to study the mechanisms of immunity in brain and spinal cord disease, in addition to autoimmunity in general. EAE is induced primarily in mice by immunisation with myelin antigens resulting in an autoimmune condition associated with paralysis of the hindlimbs. Unsurprisingly this is classified as a severe procedure under the Animals (Scientific Procedures) Act 1986.
Through funding from the NC3Rs, my research group at Queen Mary, University of London, has been able to refine the EAE model to reduce the suffering for the animals used, as well as offering scientific and economic advantages to the user. Using transgenic technology, we have focused the autoimmune damage to the optic nerve and the visual pathway so only vision is impaired, which in rodents adapted to the dark is considered a minor sense. So the improved approach offers a much needed refinement over classical EAE due to the absence of paralysis, and with a lower level of suffering this is classified as a moderate procedure in comparison to EAE (a severe procedure) under the Animals (Scientific Procedures) Act 1986.
To study neurodegeneration with this new approach we use imaging and electrophysiological techniques to monitor nerve damage in real time in the living animal. The techniques developed include optical coherence tomography (OCT), which is used frequently in patients in the clinic to monitor the progression of MS. So our novel method therefore not only offers a significant improvement over the traditional approach, but also reduces the number of animals required for the work by 50 to 70 per cent since the same animal can be monitored serially over time, without the need to cull animals at different time points.
The NC3Rs had the vision to see the translational potential of our new approach, along with the resources to allow us to exploit this model system. The benefit of the technique has yet to be filtered fully into the general research community but it has already proven useful to define therapeutic candidates for treatment trials and directly inform the development of a novel trail design in optic neuritis, which is one of the first clinical signs of MS to occur before a definitive diagnosis. A typical clinical trial in progressive MS takes between five to seven years to undertake involving hundreds of patients; using the NC3Rs-funded method, we aim to speed the assessment of candidate drugs to months rather than years and use ten times fewer people, which may help alleviate suffering in both animals and humans.
The first battle has been won and the new approach is now surfacing within the academic literature. The next challenge is to promote the global adoption and value of the model system with our international colleagues. Looks like Britain is leading the way again.
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 4:8(11).