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

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Accelerated optimisation of next generation utrophin modulators in readiness for clinical trials
Amount £163,887 (GBP)
Organisation Duchenne UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2018
 
Description Development of utrophin modulators for DMD
Amount £4,300,000 (GBP)
Organisation Summit Plc 
Sector Private
Country United Kingdom
Start 11/2013 
End 11/2019
 
Description The role of utrophin in DMD and its therapeutic potential
Amount £2,018,279 (GBP)
Funding ID MR/N010698/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2016 
End 03/2021
 
Description Utrophin modulation for the therapy of Duchenne muscular dystrophy (DMD)
Amount £196,593 (GBP)
Funding ID RA3/3073 
Organisation Muscular Dystrophy Association 
Sector Charity/Non Profit
Country United States
Start 04/2016 
End 03/2019
 
Description Utrophin modulation for the therapy of DMD 
Organisation Summit Plc
Country United Kingdom 
Sector Private 
PI Contribution We have been performing the preclinical testing of drugs for the modulation of utrophin for the therapy of DMD. Recently one of the drugs has shown signs of success in Phase 2 clinical trials.
Collaborator Contribution The partners have given advice on biology and chemistry and also covered the costs of out sourcing for toxicity studies and preclinical mouse trials. They have also funded biomarker studies. This collaborative agreement was renewed until 2019 as a result of MRC funding.
Impact This has resulted in a partnership deal with the University of Oxford to carry our preclinical work to the clinic. Phase 1 trials of one of our drugs has shown it to be safe and well tolerated. Phase 2 trials have just reported intial positive data which are very encouraging.
Start Year 2013
 
Description Action Duchenne Day with Staff and Parents with boys with DMD 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 15 people attended the lab with talks and a tour
Year(s) Of Engagement Activity 2017
 
Description Attendance for the IF Oxford Science and Ideas Festival, Explorazone: Adults Only 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Attendance for the IF Oxford Science and Ideas Festival, Explorazone: Adults Only. Oxford Town Hall, Oxford
Year(s) Of Engagement Activity 2018
 
Description Croonian Medal and Lecture 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Croonian Medal and Lecture, Royal Society of London
Year(s) Of Engagement Activity 2019
 
Description Facebook Questions and Answers "on the development of utrophin upregulation therapies for Duchenne" for the Muscular Dystrophy Campaign Charity 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I did a question and answer session on facebook for an hour on utrophin modulation therapy for therapy of DMD
Year(s) Of Engagement Activity 2016
 
Description First Women in Science Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact First Women in Science Workshop, Sidra Medicine, Doha, Qatar
Year(s) Of Engagement Activity 2018
 
Description Interview with Voice, Balliol College, Oxford. Advice to Young People 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact x
Year(s) Of Engagement Activity 2016
 
Description Keynote Speaker for Duchenne Muscular Dystrophy Awareness Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact An overview of Duchenne Muscular Dystrophy Talk for an Awareness Day, Lodnon
Year(s) Of Engagement Activity 2017
 
Description Lecture, Doha, Qatar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact "Genetic approaches to therapy for Duchenne Muscular Dystrophy" Sidra Medicine Lecture in Human Genetics, Functional Genomics 2018, Big Data to Clinic - QNCC, Doha, Qatar
Year(s) Of Engagement Activity 2018
 
Description MD UK and parents Day at the lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 15 people attended my laboratory with talks and a tour
Year(s) Of Engagement Activity 2017
 
Description Opened Avonwood Primary School (with a Science Lab), Bournemouth 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact x
Year(s) Of Engagement Activity 2016
 
Description Oxfordshire Science Festival Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact "Muscular dystrophy in the new genomic era" Talk at the Oxfordshire Science Festival held at the Museum of Natural History
Year(s) Of Engagement Activity 2016
 
Description Parental Organization DMD Serbia Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Supporters
Results and Impact "Genetic approaches to therapy of Duchenne muscular dystrophy" Talk, Parental Organization DMD Serbia, Belgrade
Year(s) Of Engagement Activity 2018
 
Description Radio Oxford and Local TV Interview on DMD 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Interview
Year(s) Of Engagement Activity 2016
 
Description Research Strategy Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Key Discussants on two topics at a Research Strategy Workshop for Muscular Dystrophy UK in London
Year(s) Of Engagement Activity 2017
 
Description Rosetrees Trust Symposium, London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk at a Symposium, London
Year(s) Of Engagement Activity 2017
 
Description Speech 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Speech for the Foodbuy Charity Fundraising Dinner in aid of the Duchenne UK and Chasing Connor's Cure
Year(s) Of Engagement Activity 2018
 
Description Talk at the WIMM, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Talk "The trials and tribulations of a career in molecular medicine" - WIMM Postdoc Association with an Evening with Professor Dame Kay E Davies - about lift, the Universe and everything else I would like to say to young scientists. WIMM, Oxford.
Year(s) Of Engagement Activity 2018
 
Description Talk, Action Duchenne Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Talk "Small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy" - Action Duchenne, Hilton Birmingham Metropole Hotel, Birmingham
Year(s) Of Engagement Activity 2018
 
Description Talk, MRC DTP Symposium, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Talk "Genetic approaches to therapy of muscular dystrophy" MRC DTP Symposium, Oxford
Year(s) Of Engagement Activity 2018
 
Description The 15th Action Duchenne International Conference, Birmingham 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Talk at a Conference
Year(s) Of Engagement Activity 2017