Human Molecular Genetics Advance Access originally published online on May 28, 2008
Human Molecular Genetics 2008 17(17):2622-2632; doi:10.1093/hmg/ddn162
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RNAi-mediated knockdown of dystrophin expression in adult mice does not lead to overt muscular dystrophy pathology
1 School of Biological Sciences, Royal Holloway – University of London, Egham TW20 0EX, UK 2 The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada M5G 1L7
* To whom correspondence should be addressed at: School of Biological Sciences, Royal Holloway – University of London, Egham, TW20 0EX, UK. Tel: +44 1784443545; Fax: +44 1784414224; Email: g.dickson{at}rhul.ac.uk
Received April 2, 2008; Revised May 16, 2008; Accepted May 23, 2008
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disorder caused by mutations in the dystrophin gene. DMD has a complex and as yet incompletely defined molecular pathophysiology. The peak of the pathology attributed to dystrophin deficiency happens between 3 and 8 weeks of age in mdx mice, the animal model of DMD. Accordingly, we hypothesized that the pathology observed with dystrophin deficiency may be developmentally regulated. Initially, we demonstrated that profound small interfering RNA-mediated dystrophin knockdown could be achieved in mouse primary muscle cultures. The use of adeno-associated virus vectors to express short-hairpin RNAs targeting dystrophin in skeletal muscle in vivo yielded a potent and specific dystrophin knockdown, but only after 
5 months, indicating the very long half-life of dystrophin. Interestingly, and in contrast to what is observed in congenital dystrophin deficiency, long-term (1 year) dystrophin knockdown in adult mice did not result, per se, in overt dystrophic pathology or upregulation of utrophin. This supports our hypothesis and suggests new pathophysiology of the disease. Furthermore, taking into account the rather long half-life of dystrophin, and the notion that the development of pathology is age-dependent, it indicates that a single gene therapy approach before the onset of pathology might convey a long-term cure for DMD.
Present address: Muscular Dystrophy Campaign, 61 Southwark Street, London SE1 0HL, UK.
Present address: Educational Development Centre, Royal Holloway – University of London, Egham TW20 0EX, UK.