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
Abstract
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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.
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.
Publications

Aartsma-Rus A
(2013)
194th ENMC international workshop. 3rd ENMC workshop on exon skipping: towards clinical application of antisense-mediated exon skipping for Duchenne muscular dystrophy 8-10 December 2012, Naarden, The Netherlands.
in Neuromuscular disorders : NMD

Anthony K
(2012)
Exon skipping quantification by quantitative reverse-transcription polymerase chain reaction in Duchenne muscular dystrophy patients treated with the antisense oligomer eteplirsen.
in Human gene therapy methods

Arechavala-Gomeza V
(2010)
Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: implication for clinical trials.
in Neuromuscular disorders : NMD

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

Arechavala-Gomeza V
(2012)
Antisense oligonucleotide-mediated exon skipping for Duchenne muscular dystrophy: progress and challenges.
in Current gene therapy

Boor I
(2007)
MLC1 is associated with the dystrophin-glycoprotein complex at astrocytic endfeet.
in Acta neuropathologica

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


Forrest S
(2010)
Personalized exon skipping strategies to address clustered non-deletion dystrophin mutations.
in Neuromuscular disorders : NMD

Garralda ME
(2013)
Emotional impact of genetic trials in progressive paediatric disorders: a dose-ranging exon-skipping trial in Duchenne muscular dystrophy.
in Child: care, health and development
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 | 03/2009 |
End | 03/2011 |
Description | Centre Grant (co PI) |
Amount | £140,000 (GBP) |
Organisation | Muscular Dystrophy UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2011 |
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 | 04/2009 |
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 |