Abstract
Splicing is a fundamental process during the expression of most human gene transcripts, with alternative splicing frequently occurring in a tissue-specific and/or developmental manner to further increase our genetic plasticity. We have shown that antisense oligomers can specifically redirect pre-mRNA processing by either excising a selected exon (blocking positive enhancer elements), or promote retention of an exon normally excluded from the mature mRNA (masking splice silencer motifs). Therapeutic alternative splicing is now in clinical trials to address Duchenne muscular dystrophy (DMD), the most common and serious form of childhood muscle wasting. Protein truncating mutations in the DMD gene that preclude synthesis of a functional protein can be removed during dystrophin pre-mRNA processing with splice switching oligomers. Targeting dystrophin exon 51 for excision will restore functional dystrophin expression in the most common subset of DMD deletion patients (about 10% of DMD boys). Following Phase 1 and 2a trials in the UK, an extended placebo-controlled study was initiated under the sponsorship of Sarepta Therapeutics in Nationwide Children’s Hospital, Columbus, Ohio. The trial has now been underway for nearly 3 years and clinically significant differences were observed, with treated boys maintaining similar levels of ambulation over the trial period. No serious adverse events have been reported and the trial remains ongoing. These promising DMD trial results have renewed enthusiasm to pursue splice intervention therapies for other disorders. Spinal muscular atrophy, cystic fibrosis, myotonic dystrophy, facioscapulohumeral muscular dystrophy, asthma, Alzheimer’s, Parkinson’s and stroke are just some of the conditions currently under investigation in our laboratory. An estimated 15% of human mutations induce aberrant splicing and splice switching oligomers may be used as a personalized genetic therapy, regardless of the mutated gene.