Molecular Analysis of Neuromuscular Diseases
Our research is focused on the understanding of muscle disease, movement and behavioural disorders. We have developed various genetic models in order to understand disease pathogenesis as well as to develop effective treatments. Our studies range from the analysis of single gene defects such as Duchenne muscular dystrophy (DMD) to the use of genetic models which provide insights into the understanding of neurodegenerative diseases such as ataxia and amytrophic lateral sclerosis (ALS). Kay Davies is co-director of the Oxford Neuromuscular Research Centre funded by MDUK.
Current Research Programmes
Duchenne muscular dystrophy is the most common genetic form of muscular dystrophy affecting 1 in 5000 boys. Although the disease is known to be caused by the absence of the cytoskeletal protein, dystrophin, no effective treatment is yet available. Any effective therapy has to replace the dystrophin-associated protein complex to reconstruct the vital link between the extracellular matrix and internal cytoskeleton.
Therapy for DMD is a challenge since the protein is large and needs to be delivered to many muscle cells in the body for therapeutic effect. However the field has reached an exciting phase where there are several strategies for therapy in clinical trials. We are taking a novel approach to treatment through the analysis of a protein closely related to dystrophin, called utrophin. Dystrophin forms a vital link between the extracellular matrix and the internal actin cytoskeleton (see below). In the absence of dystrophin and in regenerating muscle, utrophin can replace dystrophin,
Dystrophin-associated protein complex:
We have demonstrated that over expression of utrophin in the mdx animal model of the disease prevents the muscle pathology in both skeletal and cardiac muscle. Our data suggest that up-regulation of utrophin might be an effective treatment. The advantage of this approach is that it will be applicable to all patients independent of their underlying mutation.
One of the lead compounds developed with Summit Therapeutics which modulates the expression of dystrophin is called ezutromid (SMT C1100). Summit Therapeutics successfully completed Phase I trials but however, although initial data at 24 weeks looked promising, data at 48 weeks showed no clinical benefit. The trial was therefore terminated. With our colleagues in the Department of Chemistry (Professor Steve Davies and Dr Angela Russell), we are also screening for follow up next generation compounds using a new knock-in mouse model which screens the promotor region in its full genomic context. We currently have new hits which we are evaluating in the mdx mouse model.
We are also working on the development of non-invasive biomarkers for the disease so that we can monitor the effects of utrophin modulation therapy in both preclinical and clinical studies. We have recently demonstrated that developmental myosin is an excellent biomarker both for human trials and in preclinical studies in the mdx mouse. An example of one of these drugs which increases utrophin at the sarcolemma is shown below.