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A phase I/IIa clinical trial in Duchenne muscular dystrophy using systemically delivered morpholino antisense oligomer to skip exon 53

Objective

Duchenne muscular dystrophy (DMD) is a progressive, lethal muscle degenerative condition arising from the absence of dystrophin in skeletal and cardiac muscles. 65% of DMD boys have out-of-frame deletions. Modulation of pre-mRNA splicing by exon skipping is the most promising molecular intervention in DMD. 2 Phase Ib and 2 Phase IIa clinical trials (MDEX Consortium in collaboration with Sarepta Therapeutics; a Dutch Consortium) demonstrated that delivery of antisense oligonucleotides (AOs) to mediate exon skipping of exon 51 were able to return specific DMD mutations in-frame (~13% of all mutations) leading to new dystrophin protein expression after intramuscular and systemic delivery. The Dutch study of repeated 2-O-methylated phosphorothioate (2OMe) AO administration suggested limited efficacy after 5 weeks of treatment. Our MDEX Consortium study using a morpholino (PMO) AO demonstrated a clear dose response, robust dystrophin restoration and reduction of muscle inflammation after 12 weeks at doses up to 20mg/Kg, with no drug related adverse events. This, and preclinical studies focused on level of protein expression, clearly indicate that PMO have a superior therapeutic index compared to 2OMe. New PMOs are needed to target other DMD mutations. We will develop a PMO to skip exon 53 and perform a clinical trial in DMD boys using a world leading pan-European consortium. This will allow us to advance this class of PMO therapy in DMD by i. assessing the safety and efficacy of targeting another exon; ii. exploring the use of non-invasive techniques to monitor dystrophin restoration. This new PMO will be administered over 12 weeks in 3 groups, each of 4 DMD boys, receiving between 4 to 30mg/kg or placebo. If well tolerated, all boys will be treated for another 24 weeks at a dose of 30mg/kg. Safety and dystrophin restoration in a muscle biopsy at the end of this period will be the study endpoints. MRI, MRS and serum miRNA will be used to monitor muscle pathology non-invasively.

Field of science

  • /medical and health sciences/basic medicine/neurology/muscular dystrophy
  • /medical and health sciences/basic medicine/pathology
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/basic medicine/neurology/muscular dystrophy/duchenne muscular dystrophy

Call for proposal

FP7-HEALTH-2012-INNOVATION-1
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Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

UCL Elizabeth Garrett Anderson Institute for Women’s Health
Address
Gower Street
WC1E 6BT London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 147 708,62
Administrative Contact
Michael Browne (Mr.)

Participants (9)

ASSOCIATION INSTITUT DE MYOLOGIE
France
EU contribution
€ 447 367,99
Address
Boulevard De L Hopital 47-83
75651 Paris
Activity type
Research Organisations
Administrative Contact
Christelle Gaultier (Mrs.)
CONSULTANTS FOR RESEARCH IN IMAGING AND SPECTROSCOPY SCRL
Belgium
EU contribution
€ 168 373,88
Address
Chaussee De Lannoy 31
7503 Tournai
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Raymond Gilles (Dr.)
UNIVERSITY OF NEWCASTLE UPON TYNE
United Kingdom
EU contribution
€ 445 316
Address
Kings Gate
NE1 7RU Newcastle Upon Tyne
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Aleona Blinova (Ms.)
UNIVERSITA CATTOLICA DEL SACRO CUORE
Italy
EU contribution
€ 204 600
Address
Largo Gemelli 1
20123 Milano
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Filippo Leone (Mr.)
CHARLES RIVER LABORATORIES PRECLINICAL SERVICES EDINBURGH LTD
United Kingdom
EU contribution
€ 326 100,35
Address
Elphinstone Research Centre
EH33 2NE Tranent
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Ernest Larnach (Mr.)
ROYAL HOLLOWAY AND BEDFORD NEW COLLEGE
United Kingdom
EU contribution
€ 194 941
Address
Egham Hill University Of London
TW20 0EX Egham
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Rosemary Greaves (Ms.)
SYSNAV SAS
France
EU contribution
€ 316 100
Address
Rue De Montigny 57
27200 Vernon
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Eric Dorveaux (Dr.)
SAREPTA THERAPEUTICS INC CORPORATION
United States
EU contribution
€ 1 966 527,85
Address
Monte Villa Parkway - Suite 101 3450
98021 Bothell Wa
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Edward Kaye (Dr.)
GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS FOUNDATION TRUST
United Kingdom
EU contribution
€ 295 388,38
Address
Great Ormond Street
WC1N 3JH London
Activity type
Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments)
Administrative Contact
Anna Ferrant (Dr.)