This is the general strategy used for designing exon-skipping oligos for DMD; as there are 79 exons transcribed in the longest splice form of the dystrophin transcript, many different oligos are needed to address the range of mutations present in the population of people with DMD.Eteplirsen is a morpholino antisense oligomer which triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin; giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular nonsense mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (although modified by having an internal deletion consisting of both the patients original defect, as well as the therapeutically skipped exon) dystrophin. Eteplirsen is given by intravenous infusion for systemic treatment of DMD. Exon skipping is induced by eteplirsen, a charge-neutral, phosphorodiamidate morpholino oligomer (PMO) that selectively binds to exon 51 of dystrophin pre-mRNA, restoring the phase of the reading frame and enabling production of functional, but internally edited, dystrophin. The uncharged nature of the PMO helps make it resistant to biological degradation. This modified dystrophin protein produced by eteplirsen may cause a less severe form of dystrophinopathy, much like Becker muscular dystrophy. Eteplirsens proposed mechanism of action is to bind to dystrophin pre-mRNA and alter the exon splicing of the RNA so that more almost full-length dystrophin is made.
By increasing the quantity of an abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD. Nature and sequence of oligo and target
Eteplirsen is a morpholino phosphorodiamidate antisense oligomer. CTCCAACATCAAGGAAGATGGCATTTCTAG (sequence source: US FDA ETEPLIRSEN BRIEFING DOCUMENT NDA 206488),
30-mer,
20% G,
43% CG,
Predicted Tm: 88.9 °C at 10 μM oligo. Oligo complement
CTAGAAATGCCATCTTCCTTGATGTTGGAG
DMD-001 Exon 51, ENST00000357033.8 in Ensembl.org, RNA target site marked. Given that the target site is within an exon, this is likely blocking binding of an exonic splice enhancer protein and so altering splicing by interfering with splice regulation. CTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCT
CCAAA[CTAGAAATGCCATCTTCCTTGATGTTGGAG]GTACCTGCTCTGGCAGATTTCAACC
GGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGA
GGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAG

Pharmacokinetics
Following single or multiple intravenous infusions, the majority of drug elimination occurred within 24 hours of intravenous administration. Elimination half-life of eteplirsen was 3 to 4 hours. History
New Drug Applications (NDA) for eteplirsen and a similar drug drisapersen were filed with the US Food and Drug Administration (FDA) in August 2015. The Prescription Drug User Fee Act (PDUFA) goal dates for these were December 27, 2015 for drisapersen and February 26, 2016, for eteplirsen. Following FDA rejection of drisapersen, the agency announced a three-month time extension for its review of eteplirsen. The FDA panel decision was controversial because the FDA staff and the panel used a stricter standard of evidence than Sarepta and patient groups used. The FDA panel said that it was required by law to apply the standard of "substantial evidence" of effectiveness. This required randomized, controlled trials showing effectiveness of a meaningful clinical outcome, such as the ability to function in daily life.