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

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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.