Molecular Analysis of Neurological Disorders
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 have successfully completed Phase I trials with this drug and a Phase II trial has been initiated. We are working with them to determine the mechanism of action of ezumtromid which will assist us in identifying similar drugs with potentially greater efficacy. 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. An example of one of these drugs which increases utrophin at the sarcolemma is shown below.
NEURODEGENERATIVE AND BEHAVIOURAL DISORDERS
This work is in collaboration with an ERC Fellow, Dr Peter Oliver. We are investigating movement and neurodegenerative disorders through the characterisation of specific neurological mutants from the ENU mutagenesis programme at the MRC Mammalian Genetics Unit at Harwell. This has included studying models of human ataxia (robotic and moonwalker mutants) and peripheral neuropathy (trembler mutants) that have lead to the identification of potential therapeutic strategies for these disorders.
Oxidative stress in the central nervous system is a feature of some of the most common neurodegenerative disorders such as Parkinson’s disease (PD), Huntington’s disease (HD) and ALS. We have recently shown that the loss of the Oxr1 gene in bella mutant causes ataxia and cell death in the cerebellum and that Oxr1 protects neurons from oxidative stress. Increases of Oxr1 levels ameliorate the phenotype in ALS disease models.. The function of this gene in unknown; however we know it is part of the protective pathways that are induced in neurons under oxidative stress. Current work is establishing the function of Oxr1 using primary neuronal cell culture, protein interaction assays and transgenic mouse models.