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Personalised genetic medicines for inherited disorders

Wilton, S. and Fletcher, S. (2014) Personalised genetic medicines for inherited disorders. In: 5th FIP Pharmaceutical Sciences World Congress (FIP PSWC) 2014: Pharmaceutical Sciences Beyond 2020, 13 - 16 April 2014, Melbourne, VIC.


Background. Antisense oligonucleotides can redirect the pre-mRNA processing of targeted gene transcripts. Therapeutic alternative splicing can be employed excise a selected exon or enhance recognition of an exon normally excluded from the mature mRNA.

Aims. Duchenne muscular dystrophy (DMD), the most common and serious form of childhood muscle wasting, arises from protein truncating mutations in DMD that preclude synthesis of a functional protein. We aim to specifically redirect dystrophin pre-mRNA processing so that one or more exons can be excluded from the mature mRNA. Depending upon the DMD mutation, the reading frame can be restored, or intra-exonic protein truncation mutations can be bypassed, allowing an internally deleted but functional dystrophin isoform to be produced.

Methods. Targeting dystrophin exon 51 for excision should restore functional dystrophin expression in the most common subset of DMD deletion patients. An extended placebo-controlled study was initiated under the sponsorship of Sarepta therapeutics in Nationwide Children’s Hospital, Columbus Ohio.

Results. The trial has now been extended out to over 2 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. Additional oligomers are being designed to address different dystrophin mutations, and new clinical trials should be underway in 2014.

Summary. The promising DMD trial results have renewed enthusiasm to pursue splice intervention therapies for other disorders. Spinal muscular atrophy, cystic fibrosis, facioscapulohumeral muscular dystrophy, asthma, Alzheimer’s, Parkinson’s and stroke are just some of the conditions under investigation. 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.

Publication Type: Conference Item
Murdoch Affiliation: Centre for Comparative Genomics
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