Cardio-respiratory failure is the major cause of death in DMD patients, mainly due to
diaphragm and heart fibrosis. It is therefore important to understand the inflammation
process underlying these events and evaluate the potential of novel therapeutic targets.
We propose to investigate the efficacy of PKC¿ inhibitors in the treatment and/or
prevention of late stage complications of muscular dystrophy, using the mouse model
of DMD, mdx. We will examine whether and how, manipulating the immune response
in mdx, via PKC¿ inhibition, may counteract late disease hallmarks, such as diaphragm
and heart fibrosis.
We recently showed that treatment of young mdx mice with a PKC¿ inhibitor
significantly prevented limb muscle damage and improved muscle performance. Our
pilot study designed to investigate the mechanism by which PKC¿ inhibition ameliorates
muscle damage, revealed that thePKC¿ inhibitor mostly acts by inhibiting T cell
activation thereby preventing their entry into dystrophic muscle. Further, targeting T
cells with a PKC¿ inhibitor prior to the onset of muscle necrosis, significantly reduced
limb muscle necrosis and inflammation during the acute phase of the disease. Here we
propose to investigate whether PKC¿ inhibition would also be effective in ameliorating
late disease outcomes, such as diaphragm and heart fibrosis.
We will first characterize in detail the inflammatory cell components in diaphragm and
heart at different stages of muscular dystrophy, from very early at 0,5 months up to 6
months in the diaphragm and up to 10 months in the heart, in the mdx mouse model.
This information will allow us to design the optimal PKC¿ inhibitor treatment protocol
tailored to either prevent and/or ameliorate fibrotic changes in diaphragm and heart
muscle. It is hoped that the achievement of this goal will enable the development ofa
new and effective pharmacologically-based therapy to be clinically tested in DMD.
