SKIP-NMD

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

 Coordinatore UNIVERSITY COLLEGE LONDON 

 Organization address address: GOWER STREET
city: LONDON
postcode: WC1E 6BT

contact info
Titolo: Mr.
Nome: Michael
Cognome: Browne
Email: send email
Telefono: 442031000000
Fax: 442078000000

 Nazionalità Coordinatore United Kingdom [UK]
 Totale costo 7˙527˙838 €
 EC contributo 5˙512˙424 €
 Programma FP7-HEALTH
Specific Programme "Cooperation": Health
 Code Call FP7-HEALTH-2012-INNOVATION-1
 Funding Scheme CP-FP
 Anno di inizio 2012
 Periodo (anno-mese-giorno) 2012-11-01   -   2016-04-30

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    UNIVERSITY COLLEGE LONDON

 Organization address address: GOWER STREET
city: LONDON
postcode: WC1E 6BT

contact info
Titolo: Mr.
Nome: Michael
Cognome: Browne
Email: send email
Telefono: 442031000000
Fax: 442078000000

UK (LONDON) coordinator 1˙147˙708.60
2    SAREPTA THERAPEUTICS INC CORPORATION

 Organization address address: MONTE VILLA PARKWAY - SUITE 101 3450
city: BOTHELL WA
postcode: 98021

contact info
Titolo: Dr.
Nome: Edward
Cognome: Kaye
Email: send email
Telefono: +1 617 444 8424

US (BOTHELL WA) participant 1˙966˙527.90
3    ASSOCIATION INSTITUT DE MYOLOGIE

 Organization address address: BOULEVARD DE L HOPITAL 47-83
city: PARIS
postcode: 75651

contact info
Titolo: Mrs.
Nome: Christelle
Cognome: Gaultier
Email: send email
Telefono: +33 1 42 16 66 46
Fax: +33 1 42 16 96 57

FR (PARIS) participant 447˙368.00
4    UNIVERSITY OF NEWCASTLE UPON TYNE

 Organization address address: Kensington Terrace 6
city: NEWCASTLE UPON TYNE
postcode: NE1 7RU

contact info
Titolo: Ms.
Nome: Aleona
Cognome: Blinova
Email: send email
Telefono: +44 191 282 4528

UK (NEWCASTLE UPON TYNE) participant 445˙316.00
5    CHARLES RIVER LABORATORIES PRECLINICAL SERVICES EDINBURGH LTD

 Organization address address: ELPHINSTONE RESEARCH CENTRE
city: TRANENT
postcode: EH33 2NE

contact info
Titolo: Mr.
Nome: Ernest
Cognome: Larnach
Email: send email
Telefono: 441876000000
Fax: 441876000000

UK (TRANENT) participant 326˙100.34
6    SYSNAV SAS

 Organization address address: RUE DE MONTIGNY 57
city: VERNON
postcode: 27200

contact info
Titolo: Dr.
Nome: Eric
Cognome: Dorveaux
Email: send email
Telefono: +33 2 78 77 03 46
Fax: +33 2 32 64 12 40

FR (VERNON) participant 316˙100.00
7    Great Ormond Street Hospital for Children NHS Trust

 Organization address address: Great Omond Street
city: LONDON
postcode: WC1N 3JH

contact info
Titolo: Dr.
Nome: Anna
Cognome: Ferrant
Email: send email
Telefono: +44 207 8138230

UK (LONDON) participant 295˙388.38
8    UNIVERSITA CATTOLICA DEL SACRO CUORE

 Organization address address: Largo Agostino Gemelli 1
city: MILANO
postcode: 20123

contact info
Titolo: Mr.
Nome: Filippo
Cognome: Leone
Email: send email
Telefono: +39 06 30156099
Fax: +39 06 30156803

IT (MILANO) participant 204˙600.00
9    ROYAL HOLLOWAY AND BEDFORD NEW COLLEGE

 Organization address address: EGHAM HILL UNIVERSITY OF LONDON
city: EGHAM
postcode: TW20 0EX

contact info
Titolo: Ms.
Nome: Rosemary
Cognome: Greaves
Email: send email
Telefono: +44 1784 44 3019

UK (EGHAM) participant 194˙941.00
10    CONSULTANTS FOR RESEARCH IN IMAGING AND SPECTROSCOPY SCRL

 Organization address address: RUE LOUIS JAMME 24
city: LIEGE
postcode: 4020

contact info
Titolo: Dr.
Nome: Raymond
Cognome: Gilles
Email: send email
Telefono: 32478757909

BE (LIEGE) participant 168˙373.88

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

treatment    restoration    rna    efficacy    duchenne    therapeutic    dose    monitor    intervention    nmd    boys    progressive    ome    mg    administered    mdex    another    dystrophy    muscular    inflammation    gene    safety    serum    disease    therapeutics    trial    skipping    expression    protein    dmd    invasive    perform    degenerative    frame    oligonucleotide    dutch    molecular    antisense    progression    functional    exons    skip    mutations    outcome    monitoring    kg    muscle    ao    demonstrated    pmo    exon    weeks    dystrophin    trials    oligonucleotides    clinical    therapy   

 Obiettivo del progetto (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.'

Introduzione (Teaser)

RNA therapeutics is gaining ground in the treatment of many diseases. European researchers hope to show it could be a valid intervention for the treatment of Duchenne muscular dystrophy (DMD).

Descrizione progetto (Article)

DMD is a progressive muscle degenerative condition that stems from a lack of the protein dystrophin. Loss of dystrophin leads to inflammation and replacement of muscle with fibrous tissue.

Despite prenatal diagnosis, the incidence of DMD is 1 in 5 000 births due to novel mutations that arise in the dystrophin gene. The dystrophin gene is one of the largest known, with 79 different protein-coding regions referred to as exons. Mutations in one of these exons interfere with the rest of the gene being put together and producing a functional protein.

In Becker muscular dystrophy (BMD), DMD mutations still produce a shortened but functional dystrophin protein, and most patients are able to walk and have a normal lifespan. This occurs because although some exons are missing, the remaining can join together.

Based on this observation, scientists have developed a method known as exon skipping, which essentially encourages the cellular machinery to skip the mutated exon. For this purpose, they are using oligonucleotides as molecular patches to produce the shorter version of the dystrophin protein.

Prior work by the members of the EU-funded http://www.skip-nmd.eu/ (SKIP-NMD) consortium successfully demonstrated the therapeutic outcome of skipping exon 51 in clinical trials with boys with DMD. The scope of SKIP-NMD is to extend this work in other children with DMD and perform skipping of exon 53.

After finalising the optimal antisense oligonucleotide sequence, researchers have performed toxicology and pharmacology studies to prepare for the clinical trial. Good manufacturing practices- antisense oligonucleotide molecules have been produced and a clinical trial protocol has been submitted for authorisation. The study will also validate novel outcome measures and assess the role of muscle magnetic resonance imaging and spectroscopy and serum biomarkers levels as a means of monitoring therapeutic intervention.

Although antisense oligonucleotide therapy is not a cure, and for therapy to be effective it should be administered at regular intervals throughout life, it is expected that this novel therapeutic intervention will result in reduction of muscle damage and slow down disease progression. The SKIP-NMD clinical trial is expected to provide novel information on the efficacy of this novel RNA therapeutics compound and establish the role for non-invasive monitoring of disease progression.

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