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

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.