Anthony, Karen

Arechavala-Gomeza, Virginia

Bushby, Kate

Cirak, Sebahattin

Dickson, George

Feng, Lucy

Garralda, Maria Elena

Guglieri, Michela

Morgan, Jennifer

Muntoni, Francesco

Sewry, Caroline

Shrewsbury, Stephen B.

Straub, Volker

Torelli, Silvia

Wells, Dominic J.

Wilton, Stephen D.

Wood, Matthew Ja

Objective: We report biochemical efficacy and clinical safety ofa phase 1b/2 dose-ranging study of IV administered AVI-4658,an antisense morpholino oligomer which restores the readingframe and enables dystrophin expression in Duchenne musculardystrophy (DMD) patients with amenable deletions for exon 51skipping.Method: AVI-4658 was given weekly for 12 weeks by intravenousinfusions in a dose escalation study (0.5, 1.0, 2.0, 4.0, 10 and20 mg/kg) to 19 ambulant DMD patients aged 5–15 years. Theprimary study objective was safety and tolerability over the26 week study. Secondary objectives were: 1) pharmacokineticproperties, 2) ability of AVI-4658 to induce exon skipping anddystrophin expression by RT-PCR, immunohistochemistry andimmunoblotting.Results: AVI-4658 was well tolerated with no drug related seriousadverse events. We compared dystrophin levels in pre- and posttreatment (two weeks after last dose) muscle biopsies. AVI-4658induced exon 51 skipping in the first 4 cohorts, followed byboth stronger skipping and dystrophin protein expression in agenerally dose dependent, but variable, manner in boys fromcohort 3 onwards. A total of 7 subjects displayed an increase ofdystrophin expression in the post-treatment biopsy, with 3 subjectsshowing a substantial increase in positive fibers (15%, 21% and55%, respectively). Additionally dystrophin associated proteins wererestored at the sarcolemma. Analysis of the inflammatory infiltrateindicated a reduction of cytotoxic T cells in the post-treatmentmuscle biopsies in the 2 higher dose cohorts.Conclusion: We demonstrate the potential of AVI-4658 to becomea disease modifying drug in the treatment of DMD

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Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment

Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment

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