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.
Anti-inflammatory therapies for DMD are a promising option, either alone or in combination with other therapies. Currently, the main stay of DMD palliative treatment is the administration of glucocorticoids to
reduce inflammation. However, the secondary adverse effects of corticoids necessitate the search for new drugs, which requires further detailed understanding of the cellular and molecular events driving muscle wasting and fibrosis. In this context, we propose a new potential therapy to DMD, by pharmacologically targeting PKC¿, in the mdx mice model of DMD. We already demonstrated a critical
role of immune-cell intrinsic PKC¿ activity in the development of DMD by genetic manipulation; we also showed that pharmacological inhibition of PKC¿ ameliorates skeletal muscle histopathology and
performance at the early stages of the disease. In contrast to other anti-inflammatory approaches, inhibition of PKC¿ through its T cell-specific activity, should result in a modulation of the immune
response. Our encouraging reported and preliminary data thus identify PKC¿ as a novel target to reduce the immune response without the side effects associated with the drugs currently used in clinic. However, the ability of the proposed strategy to prevent the late hallmarks of the disease, such as muscle fibrosis and suboptimal regeneration capacity of MuSCs needs to be investigated with the view of translating those findings in clinic. A large effort is currently devoted to the optimization of specific and selective PKC¿
inhibitors, making a pharmacologically-based targeting of PKC¿ a reasonable promise. Based on our results, we hypothesize that PKC¿ inhibition in mdx, prevents late stage disease hallmarks, such as diaphragm and cardiac muscle fibrosis by selectively manipulating the immune response. In DMD, fibrosis is the main cause of functional loss in both skeletal and cardiac muscle, leading to severe cardiovascular defects, and it most likely arises from the deleterious activity of components of the immune response. We will thus use the C20 and the AEB071 compounds as a proof of concept in order to establish a pharmacological protocol which might be proposed as long as specific and selective PKC¿ inhibitors, with a defined therapeutic profile become available.