Lancet: Geeniterapia alkaa onnistua Duchennen lihasdystrofiassa

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60756-3/fulltex

Duchenne muscular dystrophy is a progressive, severely disabling neuromuscular disease that affects one in 3500 newborn boys and causes premature death.¹ In Duchenne muscular dystrophy, the open reading frame  (ORF) of the X-linked dystrophin gene (DMD) is disrupted by deletions (roughly 65%), duplications (10%), point mutations (10%), or other smaller rearrangements. Dystrophin is located underneath the sarcolemma and assembles with sarcolemmal proteins such as dystroglycan, α-sarcoglycan, and neuronal nitric oxide synthase (NOS) to form the dystrophin-associated glycoprotein complex. The essential function of dystrophin in muscle is to connect the subsarcolemmal cytoskeleton to the sarcolemma by binding N-terminally to F-actin and C-terminally to β-dystroglycan. Loss of dystrophin results in inflammation, muscle degeneration, and replacement of muscle with fibroadipose tissue.²

In the milder allelic Becker muscular dystrophy, dystrophin mutations do not disrupt the open reading frame, a shortened but functional dystrophin protein is produced, and most patients are able to walk into late adulthood and have a normal lifespan.³ Therefore, induction of exon skipping to restore the open reading frame (ORF)  is an attractive therapeutic strategy in Duchenne muscular dystrophy that can be achieved with splice-switching oligomers. These oligomers are typically 20–30 nucleotides in length and are complementary in sequence to regions of the pre-mRNA transcript relevant for targeted DMD exon skipping.⁴ Splice-switching oligomers targeting dystrophin exons have been successfully used to restore dystrophin expression in vitro and in various animal models of Duchenne muscular dystrophy.^{5, 6} In the mdx mouse, administration of 2′O-methyl-ribooligonucleoside-phosphorothioate (2′OMe) and phosphorodiamidate morpholino oligomers (PMOs) identified PMOs as more effective for induction of exon skipping and restoration of long-lasting dystrophin production after intramuscular or intravenous administration.⁷ In the X-linked muscular dystrophy dog, PMO administration was followed by dystrophin restoration and clinical benefit without adverse reactions.⁶

Two proof-of-principle clinical trials in patients with Duchenne muscular dystrophy, who received one intramuscular administration of either 2′OMe⁸ or PMO⁹ targeted to skip exon 51, showed efficient dystrophin restoration. More recently, in an open-label, dose-escalation study in 12 boys with Duchenne muscular dystrophy,¹⁰ weekly subcutaneous injections of PRO051, a 2′OMe splice switching oligomer, at 0·5, 2, 4, and 6 mg/kg bodyweight for 5 weeks induced skipping of exon 51 and increased dystrophin concentrations. A 12-week extension with a dose of 6 mg/kg bodyweight of PRO051¹⁰ was well tolerated and was followed by stabilisation of muscle function, but no significant improvement in a 6-min walk test. We report biochemical efficacy and clinical safety from a dose-ranging study of the first intravenous systemically administered PMO, AVI-4658, in patients with Duchenne muscular dystrophy.