Rabbit Anti-Dystrophin monoclonal antibody, clone KG2-133

Mutations in the dystrophin and sarcoglycans genes result in muscular dystrophies causing severe disability and premature death and where no effective treatment is available. New therapeutic approaches targeting secondary disease mechanisms have a strong translational potential. Dystrophic muscle damage triggers release of ATP whilst loss of ecto-ATPase activity of sarcoglycan further elevates extracellular ATP (eATP) levels. Such a high eATP activates P2X7 purinoceptors on immune cells; these contribute to chronic inflammatory and immune responses that exacerbate the dystrophic pathology. Dystrophin mutations coincide with a significant P2X7 upregulation in Duchenne muscular dystrophy (DMD) muscle and alter receptor signalling in mouse dystrophic myoblasts and myofibers. P2X7 overexpression combined with the eATP-rich environment lead to cell dysfunction and death and ultimately to ineffective regeneration. P2X7 is therefore a therapeutic target for reducing damaging inflammation and supporting the repair of dystrophic muscles. Accordingly, genetic ablation and pharmacological inhibition of the eATP-P2X7 axis alleviated dystrophic phenotypes in mouse models of dystrophinopathy and sarcoglycanopathy. Thus, P2X7 inhibitors are good candidates for rapid re-purposing for the treatment of these highly debilitating diseases. Such a therapy is not constrained by causative mutations, so it would be suitable for all patients. Moreover, it appears effective in alleviating both muscle and non-muscle symptoms.

Duchenne muscular dystrophy (DMD) is a severe and rapidly progressive hereditary muscular disease with X-linked recessive inheritance, occurring mainly in males. A complete loss of dystrophin resulted from out-of-frame deletion mutations in the DMD gene leads to Duchenne muscular dystrophy. DMD induced pluripotent stem cells (iPSCs) are a suitable cell model to study muscle development and disease mechanisms underlying muscular dystrophy and to screen novel compounds with potential therapeutic effects. We generated iPSCs from a DMD patient using non-integrating episomal plasmid vectors. The obtained iPSC lines showed ESC-like morphology, expression pluripotency markers, displayed a normal karyotype and possessed trilineage differentiation potential.