The P2X7 purinoceptor in pathogenesis and treatment of dystrophino- and sarcoglycanopathies. (April 2023)

• Record Type: Journal Article
• Authors: Gόrecki, Dariusz C.; Rumney, Robin M.H.
• Is Part Of: Current opinion in pharmacology. Volume 69(2023)
• Publication Date: 2023-04
• Subjects: Pharmacology -- Periodicals; Pharmaceutical Preparations -- Periodicals; Drug Therapy -- Periodicals; Biopharmaceutics -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Periodicals; 615.105
• DOI: 10.1016/j.coph.2023.102357
• Languages: English
• ISSNs: 1471-4892

Abstract

Abstract: Dystrophinopathy and sarcoglycanopathies are incurable diseases caused by mutations in the genes encoding dystrophin or members of the dystrophin associated protein complex (DAPC). Restoration of the missing dystrophin or sarcoglycans via genetic approaches is complicated by the downsides of personalised medicines and immune responses against re-expressed proteins. Thus, the targeting of disease mechanisms downstream from the mutant protein has a strong translational potential. Acute muscle damage causes release of large quantities of ATP, which activates P2X7 purinoceptors, resulting in inflammation that clears dead tissues and triggers regeneration. However, in dystrophic muscles, loss of α-sarcoglycan ecto-ATPase activity further elevates extracellular ATP (eATP) levels, exacerbating the pathology. Moreover, seemingly compensatory P2X7 upregulation in dystrophic muscle cells, combined with high eATP leads to further damage. Accordingly, P2X7 blockade alleviated dystrophic damage in mouse models of both dystrophinopathy and sarcoglycanopathy. Existing P2X7 blockers could be re-purposed for the treatment of these highly debilitating diseases. Highlights: Loss of dystrophin and/or sarcoglycans reduces eATP degradation and enhances P2X7 signalling in muscles. Sterile inflammation is a pathological hallmark of both DMD and sarcoglycanopathies. Mitigation of this purinergic abnormality reduces damaging inflammation and improves the dystrophic phenotype. P2X7 blockers could be rapidly re-purposed for treatment of DMD and sarcoglycanopathies.