SKIP-NMD

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

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 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.