Grant: Operating Grant

In Duchenne Muscular Dystrophy (DMD), repeated cycles of muscle fiber destruction lead to progressive paralysis and death. The basic cause of this is the lack of an essential protein located at the surface membrane of muscle fibers, due to a mutation of the dystrophin gene on the X chromosome. A promising approach to the therapy of DMD is the transfer into muscle fibers of a normal dystrophin gene. Another approach to DMD therapy is a substantial increase of an analogue of dystrophin, the protein utrophin, so that it becomes present throughout the surface membrane of muscle fibers, instead of its normal, very restricted localization. Several pieces of evidence in mouse and dog models of DMD indicate that a substantial increase of the amount of utrophin will decrease or eliminate muscle fiber damage caused by lack of dystrophin. We have previously published a means of directly increasing the amount of mouse utrophin using proteins called artificial transcription factors. In this proposal, we will use the same approach to design artificial transcription factors which target the human utrophin gene in order to increase the amounts of human utrophin. It is hoped that these may eventually be used as part of therapy for Duchenne muscular dystrophy.