RNAi-mediated knockdown of dystrophin expression in adult mice
does not lead to overt muscular dystrophy pathology.
Hum Mol Genet. 2008 May 28.
hmg.oxfordjournals.org
Ghahramani Seno MM, Graham IR, Athanasopoulos T, Trollet C,
Pohlschmidt M, Crompton MR, Dickson G.
School of Biological Sciences, Royal Holloway – University of
London, Egham, TW20 0EX, UK.
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 siRNA-mediated dystrophin knockdown
could be achieved in mouse primary muscle cultures. The use of
adeno-associated virus (AAV) vectors to express shRNAs
targeting dystrophin in skeletal muscle in vivo yielded a
potent and specific dystrophin knockdown, but only after
approximately 5 months, indicating the very long half-life of
dystrophin. Interestingly, and in contrast to what is observed
in congenital dystrophin deficiency, long-term ( approximately
1 year) dystrophin knockdown in adult mice did not result, per
se, in overt dystrophic pathology or up-regulation of
utrophin. This supports our hypothesis and suggests new
pathophysiology for 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. |
