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Human genetic disease

Cell death in the cerebellum of bella mutants
Cell death in the cerebellum of bella mutants

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), as well as mental impairment and schizophrenia.

Current Research Programmes


Duchenne muscular dystrophy is the most common genetic form of muscular dystrophy affecting 1 in 3000 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. 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. One of the lead compounds developed with Summit plc which modulates the expression of dystrophin is called SMT C1100. Summit plc have just successfully completed a Phase I trial and a Phase II trial is planned. We are working with them to determine the mechanism of action of SMT C1100 which will assist us in moving this drug into the clinic. 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.

An additional promising strategy for DMD is the delivery of DNA vectors that cause the transcriptional machinery in muscle cells to miss out the mutated exons in dystrophin responsible for DMD (exon skipping); this method generates a smaller but functional protein that will prevent the disease occurring. Using antisense oligonucleotides into U7snRNA/AAV vectors, we have shown that this ‘exon skipping’ approach can successfully restore expression of the dystrophin gene in cellular and animal models of DMD. The advantage of AAV based U7snRNA vectors are that they show more sustained expression than naked antisense oligonucleotides. This work is being carried out in collaboration with Aurelie Goyenvalle and Luis Garcia in Versailles, France.

Dystrophin-associated protein complex:

Dystrophin-associated protein complex

 Improved muscle pathology using SMT C1100 (Wild type):

Improved muscle pathology using SMT C1100 (Wild type)

Improved muscle pathology using SMT C1100 (mdx - vehicle only):

Improved muscle pathology using SMT C1100 (mdx - vehicle only)

Improved muscle pathology using SMT C1100 (mdx - SMT C1100):

 Improved muscle pathology using SMT C1100 (mdx - SMT C1100)



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. 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. We are also looking at the expression of OXR1 and related genes in human neurodegenerative disease.

The blind-drunk mutant harbours a mutation in SNAP-25, a protein essential for normal exocytosis in neuronal cells. These mice display ataxia, but also a complex behavioural profile with aspects relevant to psychiatric diseases such as schizophrenia. Recently we have been investigating the influence of the environment on this behaviour. In addition, we are examining the sleep / wake (circadian) activity of these mice, as sleep disturbance is a common symptom of schizophrenia. Our data has shown that blind-drunk mutants show disrupted circadian behaviour, allowing us to examine common mechanisms that linking fundamental synaptic pathways to rest / activity profiles in mental health. This work is also funded by the Wellcome Trust Strategic Award led by Russell Foster in the department of Clinical Neurosciences and is part of the Oxford Sleep and Circadian Neuroscience Institute (SCNi). 

Circadian disruption in the Bdr mutant:

Circadian disruption in the Bdr mutant




Our team

  • Kay Davies
    Kay Davies

    Dr Lee's Professor of Anatomy and Director of the MRC Functional Genomics Unit

  • Simon Guiraud

    Postdoctoral Research Scientist

  • Sarah Squire

    Research Assistant

  • Yixing Wu

    Postgraduate Student

  • Benjamin Edwards

    Research Assistant and Deputy Unit Laboratory Manager

  • Adam Berg

    Research Assistant

  • William Pembroke

    Postgraduate Student

  • Daria Svistunova

    Postgraduate Student

  • Lee Moir

    Research Assistant

  • Tahnee Kennedy

    Postdoctoral Research Scientist

  • Nandini Shah

    Research Assistant

  • Kenny Roberts
    Kenny Roberts

    Postgraduate Student

  • Fergus Boyles

    Postgraduate Student

  • Matthew Herbert

    Postgraduate Student

  • Stephanie Millin
    Stephanie Millin

    Postgraduate Student

  • Qingji Shen
    Qingji Shen

    Postgraduate Student

  • Katarina Vrcelj

    Postgraduate Student

  • Kieran Campbell
    Kieran Campbell

    Postgraduate Student

  • Stuart Grice
    Stuart Grice

    Postdoctoral Research Scientist

  • Cynthia Sandor

    Postdoctoral Research Scientist

  • Viola Volpato

    Postdoctoral Research Scientist

  • Frank Wessely

    Postdoctoral Research Scientist (computational)

  • Harry Clifford
    Harry Clifford

    Postgraduate Student

  • Adam Handel
    Adam Handel

    Postgraduate Student

  • Xiaoming Hu
    Xiaoming Hu

    Postgraduate Student

  • Jimena Monzon Sandoval

    Career Development Fellow in Bioinformatics

  • Caleb Webber
    Caleb Webber

    MRC Programme Leader

  • Muhammad Mohd Kassim
    Muhammad Mohd Kassim

    Postgraduate Student

  • Lee Harris

    Research Assistant

  • Sarah Hemming


  • Arran Babbs

    Research Assistant

  • Matthew Williamson
    Matthew Williamson

    Postgraduate Student

Collaborations and Funding

Related research themes