Résumé :
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RNA-modulating therapeutics such as antisense oligonucleotides (AONs) provide an innovative tool for targeted modulation of gene expression and/or to correct mutated mRNA causing life threatening disorders. An increasing number of studies show that AONs can interfere with splicing in order to induce exon skipping, enhance exon inclusion, or correct splicing mutations, can remove mutant RNA or protein domains, or block RNA expression. Prosensa Therapeutics applies AON technology to develop RNA-modulating therapies for a variety of genetic diseases, including neuromuscular disorders such as Duchenne Muscular Dystrophy (DMD). Due to the natural variety of genetic mutations in DMD, a number of AONs are needed to treat the disease. Prosensa has AONs in (pre-)clinical development for 6 different exons, expected to be applicable for treatment of about 40% of the Duchenne population. Lead compound PRO051 (GSK2402968), a 2'-O-methyl phosphorothioate oligoribonucleotide that induces exon 51 skipping, recently showed dose-dependent molecular efficacy following weekly subcutaneous administrations in 12 DMD patients in a dose-escalation phase I/II study. Novel dystrophin expression, already up to 15% of normal after 5 weeks of treatment, was observed in 60% to 100% of muscle fibers in 10/12 patients. In the follow-up 3 months open-label extension study, in which all patients received weekly 6 mg/kg PRO051 injections, PRO051 was well tolerated and showed an improvement in walking distance in the six-minute walk test. Based upon the promising results from these studies, PRO051 has now entered phase 3 in collaboration with GlaxoSmithKline.
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