title: P2RX7 purinoceptor: a therapeutic target for ameliorating the symptoms of duchenne muscular dystrophy.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP-P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target.
  
  
  RESULTS
  Using a combination of molecular, histological, and biochemical methods and behavioral analyses in vivo we demonstrate, to our knowledge for the first time, that genetic ablation of P2RX7 in the DMD model mouse produces a widespread functional attenuation of both muscle and non-muscle symptoms. In dystrophic muscles at 4 wk there was an evident recovery in key functional and molecular parameters such as improved muscle structure (minimum Feret diameter, p < 0.001), increased muscle strength in vitro (p < 0.001) and in vivo (p = 0.012), and pro-fibrotic molecular signatures. Serum creatine kinase (CK) levels were lower (p = 0.025), and reduced cognitive impairment (p = 0.006) and bone structure alterations (p < 0.001) were also apparent. Reduction of inflammation and fibrosis persisted at 20 mo in leg (p = 0.038), diaphragm (p = 0.042), and heart muscles (p < 0.001). We show that the amelioration of symptoms was proportional to the extent of receptor depletion and that improvements were observed following administration of two P2RX7 antagonists (CK, p = 0.030 and p = 0.050) without any detectable side effects. However, approaches successful in animal models still need to be proved effective in clinical practice.
  
  
  CONCLUSIONS
  These results are, to our knowledge, the first to establish that a single treatment can improve muscle function both short and long term and also correct cognitive impairment and bone loss in DMD model mice. The wide-ranging improvements reflect the convergence of P2RX7 ablation on multiple disease mechanisms affecting skeletal and cardiac muscles, inflammatory cells, brain, and bone. Given the impact of P2RX7 blockade in the DMD mouse model, this receptor is an attractive target for translational research: existing drugs with established safety records could potentially be repurposed for treatment of this lethal disease.
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sinadinos
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Christopher N J
authors.initials: CN
authors.lastname: Young
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Rasha
authors.initials: R
authors.lastname: Al-Khalidi
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.affiliation: Departments of Surgery, Immunology, and Bioengineering, School of Medicine, University of Pittsburgh, Pittsburg, Pennsylvania, United States of America.
authors.forename: Paweł
authors.initials: P
authors.lastname: Kalinski
authors.affiliation: School of Engineering, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Shafini
authors.initials: S
authors.lastname: Mohamad
authors.affiliation: Platform of Behavioural Analysis (SCAC), University of Rouen, Mont-Saint-Aignan,Rouen, France.
authors.forename: Léonore
authors.initials: L
authors.lastname: Floriot
authors.affiliation: Platform of Behavioural Analysis (SCAC), University of Rouen, Mont-Saint-Aignan,Rouen, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Henry
authors.affiliation: School of Engineering, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tozzi
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Taiwen
authors.initials: T
authors.lastname: Jiang
authors.affiliation: INSERM U982, Plate-Forme d'Imagerie PRIMACEN, IRIB, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Wurtz
authors.affiliation: Platform of Behavioural Analysis (SCAC), University of Rouen, Mont-Saint-Aignan,Rouen, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Lefebvre
authors.affiliation: Genomics of Adaptive Immunity Lab, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry and Pirogov Russian National Research Medical University, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Shugay
authors.affiliation: School of Engineering, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Jie
authors.initials: J
authors.lastname: Tong
authors.affiliation: INSERM U982, Plate-Forme d'Imagerie PRIMACEN, IRIB, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Arkle
authors.affiliation: Platform of Behavioural Analysis (SCAC), University of Rouen, Mont-Saint-Aignan,Rouen, France; National Center of Scientific Research (CNRS), Caen, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: doRego
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Dariusz C
authors.initials: DC
authors.lastname: Górecki
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C546469:P2rx7 protein, mouse; D058486:Receptors, Purinergic P2X7