Neuromuscular disease
Modulation of utrophin for the treatment of Duchenne Muscular Dystrophy
With Professor Dame Kay E. Davies (Department of Physiology, Anatomy and Genetics) and Professor Steve Davies (Department of Chemistry), University of Oxford

It has been shown that utrophin, the autosomal homologue of dystrophin, can compensate for the lack of functional protein in Duchenne Muscular Dystrophy (DMD). The regulation of the transcriptional activity of the utrophin gene has been studied and multiple promoter elements identified that may serve as viable drug targets for pharmacological therapy of DMD, through modulation of utrophin.


The dystrophin protein complex

Following previous work in the group which led to the development of ezutromid, we have developed a new drug screen using improved in vitro and in vivo screening tools, with the objective being to discover Best-in-Class molecules for the modulation of utrophin. Ezutromid recently completed a Phase 2 clinical trial in patients. Our work continues to define ezutromid’s target and mechanism of action to support our development of potentially superior new drugs and an understanding of how the compound modulates the utrophin gene. Screening has recently identified a novel and potentially superior compound hit series with distinct structural and mechanistic differences with encouraging activity and drug-like properties. Current efforts within the group are focused on optimising these promising new hits, as well as the use of proteomic technologies to investigate compound mode of action and molecular target. Our overarching aim is to develop a pipeline of Next Generation molecules to deliver First-in-Class and Best-in-Class therapies for all DMD Patients.

(1) Guiraud, S.; Squire, S. E.; Edwards, B.; Chen, H.; Burns, D. T.; Shah, N.; Babbs, A.; Davies, S. G.; Wynne, G. M.; Russell, A. J.; Elsey, D.; Wilson, F. X.; Tinsley, J. M.; Davies, K. E. Second-generation compound for the modulation of utrophin in the therapy of DMD. Hum. Mol. Genet. 2015, 24 (15), 4212–4224.
(2) Russell, A. J. and Wynne, G. M. in Orphan Drugs and Rare Diseases, Palmer, M. and Pryde, D. (Ed.), Royal Society of Chemistry, 2014, ISBN: 978-1-84973-806-4.

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The UtroDMD Alliance, a cross-sectorial collaboration involving the University of Oxford, Summit Therapeutics, the Medical Research Council, the Muscular Dystrophy Association and Muscular Dystrophy UK was established in 2013 to identify and develop the next generation utrophin modulators.

Frataxin upregulators for Friedriech's Ataxia
With Professor Richard Wade-Martins (Department of Physiology, Anatomy and Genetics, University of Oxford) and Professor Andrea H. NĂ©meth (Division of Clinical Neurology, University of Oxford)

Friedreich’s Ataxia (FRDA) is the most common recessive ataxia and it is characterised by progressive neurodegeneration and heart disease. In the majority of patients FRDA is caused by the presence of a GAA repeat expansion in intron 1 of the frataxin gene (FXN) which lead to reduced levels of frataxin, a nuclear-encoded mitochondrial protein. The reduction in frataxin protein leads to iron-sulfur cluster (ISC) deficiency, mitochondrial iron accumulation and increased susceptibility to oxidative stress.


Currently, there is no approved treatment for FRDA. Our aim is to develop a pharmacological therapy for FRDA through increasing frataxin expression thereby addressing the primary molecular defect. In collaboration with Professor Richard Wade-Martins we have used a recently developed reporter cell model of FRDA to identify promising small molecules which increase frataxin expression, one of which (C5) elevates FXN expression by 1.5-2-fold in primary lymphocytes from FDRA patients.

(1) Lufino, M. M. P.; Silva, A. M.; Németh, A. H.; Alegre-Abarrategui J.; Russell A. J.; Wade-Martins, R. A. A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds. Human Mol. Genet. 2013, 22, 5173–5187.