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.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscle wasting disorder. Patients are wheelchair-bound by the age of 12 and die from respiratory failure or cardiomyopathy in their twenties. DMD is caused by the absence of the cytoskeletal protein dystrophin at the sarcolemma which makes it more susceptible to contraction-induced injury.
There is currently no effective treatment for DMD. The strategy we are taking is to modulate the expression of the dystrophin related protein utrophin which can compensate for the missing dystrophin. This approach is applicable to all patients whatever their mutation.
We will identify lead candidate small molecules for the modulation of utrophin expression by high through-put screening of dystrophin deficient immortalised mouse muscle cell lines. Our initial work has led to a first-in-class agent, SMT C1100, for the pharmacological modulation of utrophin which is entering a Phase Ib clinical trial. However, we now need to identify and develop best in class compounds to improve on current drug effectiveness. We will optimise any hits from the cell lines using medicinal chemistry and in human DMD cell lines. We will then assess lead candidates in vivo in the mdx mouse model of the disease. Promising candidate molecules will be assessed for their effect on the muscle pathology using histopatholgical and molecular analysis, assays of eccentric contraction in EDL muscle and MRI studies of the heart. We will analyse biomarkers for the disease such as miRNAs, FN1 and MMP9. We will also determine the mechanism of action of drug candidates which may allow the development of other molecular targets. Our aim is to have generated lead drug candidates that by the end of the five years of this basic preclinical work can be taken into the clinic by Summit Therapeutics.

The aim of this programme is to develop new drugs which modulate the expression of utrophin for the therapy of Duchenne muscular dystrophy (DMD). This is important because there is currently no effective treatment for DMD. In view of the fact that this disease is one of the most common recessive disorders in all populations, there is a real unmet clinical need. (It is estimated that in the developed territories of the world, there are 50,000 patients). One such drug which we have developed, SMT C1100, is already in Phase 1 trial, and it is our endeavour to progress additional drugs, potentially with better attributes such as potency or more favourable drug like properties, to move into clinical development by the end of the funding period of the grant in five years' time. This treatment has the potential to improve the quality of life of many DMD patients worldwide since it is applicable to all DMD patients regardless of their dystrophin mutation.
The treatment will be more effective in young patients, therefore the development of new-born screening for DMD could be of major importance. The PI is working with Muscular Dystrophy UK to lobby policy makers to help ensure that this could be introduced once an effective therapy becomes available.
Part of this work is funded in partnership with Summit Therapeutics and Muscular Dystrophy UK, Muscular Dystrophy Association USA, covered by an Alliance agreement set up through Isis Innovation and Research Services at the University of Oxford. This arrangement ensures that all on-going research activities are coordinated for maximum productivity and that patients and patient organisations are kept informed of developments. The development of new drug candidates and further clinical trials emanating from the UtroDMD Alliance may have significant impact on the lives of DMD patients. The programme is MRC-led and would not be possible without this Alliance of funders as it depends on a collaboration of expertise from gene to clinical trial.
The intellectual property arrangements are handled by Isis Innovation at the University. There is currently an exclusive arrangement of commercial exploitation through Summit Therapeutics (see MICA form). Summit Therapeutics is a UK-based biotechnology company, and this work would therefore benefit the UK economy in the longer term.
The staff working on the grant will be trained not only in the molecular techniques associated with the research programme but also in the rigour of reporting required for the development of a new drug. This will lead to employment prospects not only in academia but also in the biotechnology and large pharma sector.