A phase I/II clinical trial in Duchenne muscular dystrophy using systemically delivered antisense oligonucleotides

Lead Research Organisation: University College London
Department Name: Institute of Child Health


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Technical Summary

Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disorder, arises from mutations in the dystrophin gene. Antisense oligonucleotide (AO) therapy has the potential to restore effectively the production of dystrophin, the defective protein, in 60% of DMD. This could result in increased life expectancy through improved muscle survival and function. Members of this Consortium have demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. After having demonstrated proof-of-principle in human cell culture and animal model studies, we are currently involved in a Department of Health funded phase I/II trial aimed at assessing safety and efficacy of acutely administered AOs in DMD boys with deletions that can be rescued by skipping dystrophin exon 51.

The aim of the current proposal is to perform a repeated administration, systemic (IV) delivery phase I/II trial in 2 groups of individuals with DMD and different deletions, in whom dystrophin restoration could be achieved by using 2 different AOs. Indeed recent animal work indicates that repeated administration of IV AO is associated with the significant restoration of dystrophin expression in most muscles. In parallel, further laboratory studies will be focused on developing AO which could potentially restore dystrophin expression in most DMD mutations; and perfection methods of systemic delivery so that lower dosage of AO could be used.
This Consortium, reporting to a Scientific Board, will ensure directed progress and enable scientists to adapt research where necessary to achieve the desired goal of effective genetic therapy for individuals affected by DMD.


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Arechavala-Gomeza V (2012) Correspondence: Measuring dystrophin-faster is not necessarily better. in Nature reviews. Neurology

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Cazzella V (2012) Exon 45 skipping through U1-snRNA antisense molecules recovers the Dys-nNOS pathway and muscle differentiation in human DMD myoblasts. in Molecular therapy : the journal of the American Society of Gene Therapy

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Muntoni F (2011) Targeting RNA to treat neuromuscular disease. in Nature reviews. Drug discovery

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Read J (2010) Psychosocial adjustment in siblings of young people with Duchenne muscular dystrophy. in European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society

Description Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy (co PI)
Amount £2,468,621 (GBP)
Funding ID 091982/Z/10/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
Description Centre Grant (PI)
Amount £450,000 (GBP)
Organisation Muscular Dystrophy UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2009 
End 03/2011
Description Centre Grant (co PI)
Amount £140,000 (GBP)
Organisation Muscular Dystrophy UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2013
Description Contribution towards research Therapist to support clinical trials (PI)
Amount £11,535 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 05/2009 
End 04/2011
Description MRC Translation Research Centre (ICH PI)
Amount £409,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2013 
End 12/2017
Title DMD patients 
Description DMD patients biological material (primary cell cultures) 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Publications 
Title IHC quantitation 
Description to quantify the amount of positive dystrophin fibres in tissue 
Type Of Material Data analysis technique 
Year Produced 2009 
Provided To Others? Yes  
Impact assists in the efficacy outcome of the clinical trial. Peer reivewed publications. 
Title muscle MRI 
Description We correlated muscle MRI to histological findings in muscular dystrophy patients 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact peer review publication 
Description study of AVI-4658 to induce dystrophin expression in DMD patients 
Organisation Sarepta Therapeutics Inc.
Country United States 
Sector Private 
PI Contribution Since 2005 Muntoni is the PI of the multidisciplinary MDEX Consortium to promote collaborative translation research for Duchenne muscular dystrophy (www.mdex.org.uk). This consortium has already deleivered two experimental therapies using antisense oligonucleotides (Kinali etal, Lancet neurology 2009; Cirak et al, Lancet 2011). In 2011 additional funds from the AFM (French Association for Myopathies) allowed the MDEX consortiumto extend its range of collaboration to France with groups in Paris and Montpellier (now International MDEX). Recently (2011) the MDEX Consortium has also received funding from the Wellcome Trust of Health for preclinical optimisation and assessment of the safety and efficacy of a new generation of antisense oligonucleotides in Duchenne muscular dystrophy. In 2008 Muntoni contributed, with his move from Imperial College to UCL, to the application to MRC for a translation research centre in neuromuscular diseases (Hanna-PI, Muntoni-deputy director) which links London and newcastle. The centre has been highly successful and metrics of success are available on the MRC Centre MRC webpages. Between 2007 and 2011, Muntoni has been one of the PIs of the EU funded TREAT-NMD network of excellence, and resonsible for the translation research aspects of duchenne muscular dystrophy. Muntoni is currently involved in 2 additional EU funded initiatives as a co-PI.
Collaborator Contribution AVI, now Sarepta, provided clinical grade study drug
Impact An intramuscular phasel/ll clinical trial in seven DMD boys from October 2007-March 2009. PubMed ID 19713152 A systemic phasel/ll clinical trial in 19 DMD boys in two centres in the UK from January 2009-April 2010. PubMed ID 21784508
Start Year 2006
Title Eteplirsen 
Description The antisense oligonucleotide developed and used by our consortium in Phase Ib/IIa studies as part of the MRC funded activity is undergoing further IIb study by the company AVI, now Sarepta 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact now in IIb studies 
URL https://clinicaltrials.gov/show/NCT00844597
Description Dissemination articles for advocacy groups magazines 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Articles and interviews published in Action Duchenne and in Muscular Dystrophy Campaign UK Charities. The same for Muscular Dystrophy Association USA, and for MDA Australia, and for Association Francaise Myopathies.

Patient queries, request of more infromation/ clarification. Contact with industry
Year(s) Of Engagement Activity 2006,2007,2008,2009
Description Dissemination for Industrial partners 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Information regarding disease course and therapeutic strategies

improved awareness from industrial partners
Year(s) Of Engagement Activity 2008,2009
Description EMEA - TREAT-NMD meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Meeting at EMEA organised by me (but hosted at EMEA) to discuss personalised medicine for DMD

workshop report to published
20347306 Muntoni F (May, 2010) The development of antisense oligonucleotide therapies for Duchenne muscular dystrophy: report on a TREAT-NMD workshop hosted by the European Medicines Agency (EMA), on September 25th 2009., Neuromuscular disorders : NMD 20, 5, 355-62
Year(s) Of Engagement Activity 2009
Description House of Parliament presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Policymakers/politicians
Results and Impact Presentation to the all parliament group workforce on muscular dystrophy

Improved awareness of politicians
Year(s) Of Engagement Activity 2008,2009
Description MDEX website (http://www.mdex.org.uk/) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact website information and updates of MDEX Consortium activity http://www.mdex.org.uk/

request for information from interested parties
Year(s) Of Engagement Activity 2008,2009,2010
Description NIH/FDA conference on antisense oligonucleotide therapies in neuromuscular disease, Washington September 27-28, 2010 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact attended by representatives from FDA, NIH, industry, academics and parent organisation involved in Antisense Oligonucleotide Therapies in Neuromuscular Disorders

Presented concluding remark lecture on 'Lessons on Development of AON drugs for Neuromuscular Disease'.
Year(s) Of Engagement Activity 2010
Description parent organisation meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact presentations by various scientists and laypersons associated with DMD

attendance of experts in the field of DMD
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011