Givinostat

Givinostat is a histone deacetylase inhibitor. The precise mechanism by which givinostat exerts its therapeutic effects in patients with DMD is unknown.

Histone deacetylases (HDACs), as the name implies, regulate the deacetylation of various proteins. The acetylation and deacetylation of histone proteins causes an increase or decrease in gene expression, respectively, with the latter function governed by HDACs. The balance between levels of histone acetylation and deacetylation plays a key role in the modulation of gene transcription and governs numerous developmental processes, being involved in the regulation of various genes associated with signal transduction, cell growth, and cell death, as well as diseases like cancers. HDACs can deacetylate non-histone proteins, such as p53, thereby also regulating their activity.

Several HDAC isoforms have been implicated in skeletal muscle remodeling - under both physiological and pathological conditions - which serve to regulate fiber type specification, muscle fiber size and innervation, metabolic fuel switching, muscle development, insulin sensitivity, and exercise capacity. This gave rise to interest in HDACs as a potential target in the treatment of muscular dystrophies, including Duchenne Muscular Dystrophy (DMD). Consistently, HDAC expression and activity have been found altered in muscular dystrophies, suggesting a role for these enzymes in the progression of the disease. The inhibition of these enzymes by HDAC inhibitors such as givinostat contributes to the preservation of muscle force and morphology.