Dystrophin knockdown mice suggest that early, transient dystrophin expression might be enough to prevent later pathology.

Abstract

A key issue in Duchenne muscular dystrophy (DMD) gene therapy is whether we need to keep a functional dystrophin expression throughout the entire life span of the patients. Answer to this question will have significant impact on a number of therapeutic approaches, such as oligonucleotide-mediated exon skipping and protein therapy. A recent study by Ghahramani Seno et al provided a clue to this important question (1). The authors applied AAV-mediated RNAi to knockdown dystrophin expression in the tibialis anterior (TA) muscle of 1-m-old C57Bl/10 mice. Dystrophin level was reduced to undetectable levels (by immunohistostaining) four months later. Dystrophin-associated proteins were also reduced. Surprisingly, utrophin was not up-regulated. What is even more surprising is that the authors did not see the characteristic dystrophic muscle pathology after one-year long dystrophin knockdown.