Extracellular ATP and T regulatory cells: new therapeutics targets in alpha-sarcoglycan deficient muscular dystrophy (LGMD2D)

Limb Girdle Muscular Dystrophy 2D (LGMD2D) is an inherited disorder characterized by progressive weakness and degeneration of skeletal muscle, loss of ambulation, respiratory insufficiency and often premature death. The disease results from genetic defect in the alpha-sarcoglycan (a-SG) gene, encoding a muscle membrane associated protein. A specific pharmacological treatment is currently not available. In LGMD2D, the instability of the sarcolemma results in a series of secondary degenerative processes such as chronic inflammation that aggravate disease progression. In this scenario, the extracellular ATP (eATP) issued by the muscle fibers necrosis, induces prolonged activation of purinergic P2X(1-7) receptors determining a direct effect linked to altered intracellular calcium homeostasis and an indirect effect through the 'triggering 'the initial phase of the immune response and inhibition of regulatory T cells (Treg) to immunosuppressive action. Our preliminary data show that blockade of the eATP/P2X purinergic signalling by a non-selective purinoceptor antagonist delayed the progression of the dystrophic phenotype and dampened the local inflammatory response in Sgca mice (an animal model of LGMD2D) with an increase in Treg cells. The final goal of this project is to define the therapeutic potential of targeted modulation of eATP/purinoceptors axis and its role in the stimulation of Treg adaptive immunity in LGMD2D. The significance of the project is represented by the possibility of developing a new therapeutic strategy in the child's muscular dystrophy focused on the inflammatory response that could be used in conjunction with gene and or cell therapy in the future.