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

Sebahattin Cirak, Virginia Arechavala-Gomeza, Michela Guglieri, Lucy Feng, Silvia Torelli, Karen Anthony, Maria Elena Garralda, Dominic J. Wells, George Dickson, Matthew Ja Wood, Stephen D. Wilton, Volker Straub, Stephen B. Shrewsbury, Caroline Sewry, Jennifer Morgan, Kate Bushby, Francesco Muntoni

Research output: Contribution to JournalAbstractpeer-review

Abstract

Objective: We report biochemical efficacy and clinical safety of
a phase 1b/2 dose-ranging study of IV administered AVI-4658,
an antisense morpholino oligomer which restores the reading
frame and enables dystrophin expression in Duchenne muscular
dystrophy (DMD) patients with amenable deletions for exon 51
skipping.
Method: AVI-4658 was given weekly for 12 weeks by intravenous
infusions in a dose escalation study (0.5, 1.0, 2.0, 4.0, 10 and
20 mg/kg) to 19 ambulant DMD patients aged 5–15 years. The
primary study objective was safety and tolerability over the
26 week study. Secondary objectives were: 1) pharmacokinetic
properties, 2) ability of AVI-4658 to induce exon skipping and
dystrophin expression by RT-PCR, immunohistochemistry and
immunoblotting.
Results: AVI-4658 was well tolerated with no drug related serious
adverse events. We compared dystrophin levels in pre- and posttreatment (two weeks after last dose) muscle biopsies. AVI-4658
induced exon 51 skipping in the first 4 cohorts, followed by
both stronger skipping and dystrophin protein expression in a
generally dose dependent, but variable, manner in boys from
cohort 3 onwards. A total of 7 subjects displayed an increase of
dystrophin expression in the post-treatment biopsy, with 3 subjects
showing a substantial increase in positive fibers (15%, 21% and
55%, respectively). Additionally dystrophin associated proteins were
restored at the sarcolemma. Analysis of the inflammatory infiltrate
indicated a reduction of cytotoxic T cells in the post-treatment
muscle biopsies in the 2 higher dose cohorts.
Conclusion: We demonstrate the potential of AVI-4658 to become
a disease modifying drug in the treatment of DMD.
Original languageEnglish
JournalNeuromuscular Disorders
Publication statusPublished - 2011

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