Lifestyle
Neuromuscular Diseases
Head of Group: Professor Dominic Wells MA VetMB PhD MRCVS
The group is involved in the development of treatments for a range of neuromuscular diseases with particular emphasis on Duchenne muscular dystrophy (DMD) and amyotrophic lateral sclerosis (ALS). Mouse models of neuromuscular disease, e.g. the mdx mouse for DMD and the SOD-1G93A mouse for ALS, are used to test the effects of various potential therapeutic agents on neuromuscular physiology and pathology. Such treatments include gene therapies, compounds to block or delay the development of pathology and drugs to address the consequences of pathology. Emphasis is placed on treatments that have potential to be translated to human clinical trial and the group is part of the MDEX Consortium that has taken antisense exon-skipping into two clinical trials in DMD patients.
Exon-skipping:
Most mutations that cause DMD, an X-linked fatal progressive muscle disorder, destroy the open reading frame thus preventing translation of the information downstream of the mutation. This results in the failure to produce an essential protein, dystrophin, in skeletal and cardiac muscle. This in turn leads to repeated muscle damage associated with muscle contraction and loss of muscle fibres with progressive fibrosis. An allelic condition, Becker muscular dystrophy (BMD), retains the open reading frame resulting in the production of an internally partially deleted dystrophin that retains some function. Indeed some BMD patients have very mild symptoms and some families have been described that carry small deletions within dystrophin without any clinical symptoms. Antisense oligonucleotide therapy for DMD is directed at excluding one or more additional exons associated with the site of the mutation to restore the open reading frame and the production of dystrophin. Because the choice of antisense sequence depends on the site of the mutation, this approach is an example of personalised medicine although some patients share the same or very similar mutations.
Figure 1 is a transverse muscle section showing restoration of dystrophin expression in some of the muscle fibres of mdx muscle following injection of a PMO antisense oligomer that excludes exon 23, the site of a premature stop mutation.
Figure 2 shows partial restoration of the ability to withstand eccentric exercise (lengthening contractions) in mdx muscle following treatment with a PMO antisense oligomer that excludes exon 23
Recent example papers:
Sharp, P, Bye-A-Jee H & D J Wells (2010) Physiological characterization of muscle strength with variable levels of dystrophin restoration in dystrophic mdx mice following local antisense therapy. Mol Ther (in press).
Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE & F Muntoni (2009). Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 8(10):918-28
Sharp, P.S., Akbar, T., Bouri, S., Senda, A., Joshi, K., Chen, H-J., Latchman, D.S., Wells, D.J. & J de Belleroche (2008). Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression. Neurobiol Dis. 30(1):42-55.
Foster, H, Sharp, P, Trollet, C, Athanasopoulos, T, Graham, I, Foster, K, Wells, DJ & Dickson, G. (2008). Codon optimisation of microdystrophin improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol Ther. 16(11):1825-32.
Current group members
Postdocs:
Dr Maria Psatha
Dr Sofia Muses
PhD students:
Ms Hannah Lomas
Ms Nazanin Rahmani Kondori
The MDEX Consortium was formed to develop and testtreatments for Duchenne muscular dystrophy. In the last few years the MDEX Consortium has focussed on the use of antisense oligonucleotides to modify the exon inclusion from the primary transcript to restore production of the essential muscle protein dystrophin. Originally the work of the MDEX Consortium was funded bythe Department of Health (UK)in2005. For further information go to: http://www.mdex.org.uk/