Exon skipping and Duchenne muscular dystrophy: A clinical trial update
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The severe muscle wasting disease, Duchenne muscular dystrophy (DMD), arises from protein truncating mutations in the DMD gene that preclude synthesis of a functional protein. Antisense oligonucleotides have been designed to redirect dystrophin pre - mRNA processing so that an exon can be specifically excluded from the mature mRNA. We have developed a morpholino oligomer that excises dys trophin exon 51, and should restore functional dystrophin expression in the most common subset of DMD deletion patients. An extended placebo - controlled study was initiated in Columbus Ohio and this oligomer, now called Eteplirsen, has been administered int ravenously to trial participants on a weekly basis at doses of 30mg/kg or 50 mg/kg. After 24 weeks administration, boys receiving Eteplirsen were unequivocally synthesizing dystrophin, but no clinically significant benefits were observed compared to the pl acebo group (rolled over to open label after 24 weeks). However, after 36 and 48 weeks treatment, statistically significant differences in the 6 minute walk test were seen in the treated groups, when compared to the placebo/delayed treatment cohort. The dr ug is well tolerated and has not been associated with any adverse effects. The trial is now being extended into late 2013. Additional oligomers are being designed to address different dystrophin mutations, and new clinical trials should be underway in 2013 . The promising DMD trial results have renewed enthusiasm to pursue splice intervention therapies for other disorders. 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:||Journal Article|
|Murdoch Affiliation:||Centre for Comparative Genomics|
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