Background
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder that leads to muscle wasting. Givinostat, a pan-histone deacetylase inhibitor currently in a phase III clinical trial for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes compensatory muscle regeneration in mdx mice.
Objectives
This study was aimed at evaluating the effect of a long-term (15 weeks) oral treatment with Givinostat administered in combination with Prednisone in the mdx murine model.
Approach
On the basis of the results of a previous dose-response experiment performed in our Laboratories, we chose the sub-optimal dose of Givinostat (25 mg/Kg) to be administered with Prednisone (1 mg/Kg) in order to detect possible additive/synergistic effects.
The efficacy of the different treatments was evaluated by run to exhaustion, maximal forelimb strength and open field tests. We collected muscle samples to evaluate different biological parameters ex vivo. Cross sectional area frequency distribution on hematoxylin/eosin stained sections and fibrosis (%) on Sirius Red stained sections, were evaluated microscopically in gastrocnemius, tibialis anterior, triceps brachii, diaphragm and heart. Immunohistochemistry analysis was done on the same muscles to evaluate membrane integrity, macrophage (M1 and M2) and lymphocytes (T and B) infiltrate.
Results
The results obtained so far (9 weeks of treatment) indicate that Givinostat increased both maximal normalized strength and run to exhaustion performance. Prednisone is effective, but less than Givinostat.
Histological and immunohistochemical analysis are in progress.
Conclusions
The efficacy of Givinostat and of Prednisone on the different functional tests is confirmed qualitatively. A quantitative evaluation will be done on the whole dataset at the end of the experiment (15 weeks of treatment).