MICA: The role of utrophin in DMD and its therapeutic potential

Duchenne muscular dystrophy (DMD) is a devastating progressive muscle wasting disease caused by the absence of a large protein, dystrophin, in all muscle cells of patients. Generally, only boys are affected, and girls are carriers of the disease because the gene is located on the X chromosome. (Boys have only one X chromosome whereas girls have two, and therefore have a normal X chromosome to compensate). Patients are typically wheelchair bound by the age of 12 and die from respiratory failure or cardiomyopathy in their twenties. More than 65% of DMD patients have portions of the gene missing. Normally, dystrophin associates with other proteins at the muscle membrane to form the dystrophin-associated protein complex (DAPC). In the absence of dystrophin, the DAPC fails to form, and the muscle membrane becomes more susceptible to contraction-induced injury. As a consequence of this, muscle fibres die and are replaced by fibre-like tissue. There is currently no effective treatment for DMD, and because of its frequency in all populations, there is a real unmet clinical need. It is estimated that in the developed territories of the world, there are at least 50,000 DMD patients. Pharmacological treatments are being developed, and although many of them will slow the progression of the disease, there may be significant long term side effects. Genetic approaches target the mutation directly and are showing very promising progress. Examples include viral delivery of dystrophin, exon skipping and termination codon read-through. These treatments are in clinical trials but challenges remain in efficacy, delivery to all muscles including the heart,and the latter two approaches are mutation-dependent. For example, exon-51 skipping targets 13% of patients and stop codon read-through only 12% of boys with DMD. We discovered some years ago through research funded by MRC that there is another protein, utrophin, which is normally present at low levels in adult muscle. We demonstrated that if utrophin levels are increased in the mdx mouse model of the disease, the muscle pathology is improved. Our strategy for DMD therapy is therefore to modulate the expression of this dystrophin-related protein, utrophin, using small chemical molecules. This approach is applicable to all patients because it is not mutation-dependent. Furthermore, an orally-administered drug can potentially target all affected muscle types, including heart and diaphragm. We are now at an exciting stage where we have proof of principle of the utrophin modulation approach. We have several chemical series which increase utrophin levels from our high through-put screens. However, these drugs need to be optimised and their effects characterised in detail in the mdx mouse. The programme requires close collaboration with chemists, molecular biologists and Summit Therapeutics. Summit Therapeutics are currently performing Phase 1b trials in patients with our first candidate drug, SMT C1100. However, we now need to identify and develop follow-up compounds to improve on current drug effectiveness and we need to understand more about this therapy works. This work will be part of the UtroDMD Alliance of which MRC is a member and which includes the Muscular Dystrophy Association USA and Muscular Dystrophy UK. This Alliance of funders allows us to work seamlessly with patients groups and Summit Therapeutics to deliver these molecules to the clinic.