P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy

Sinadinos, A and Young, CNJ and Al-Khalidi, R and Teti, A and Kalinski, P and Mohamad, S and Floriot, L and Henry, T and Tozzi, G and Jiang, T and Wurtz, O and Lefebvre, A and Shugay, M and Tong, J and Vaudry, D and Arkle, S and doRego, JC and Górecki, DC (2015) P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy. PLoS Medicine, 12 (10). ISSN 1549-1277

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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. Methods and Findings: 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.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Sinadinos, A Young, CNJ Al-Khalidi, R Teti, A Kalinski, P pak5@pitt.edu PAK5 Mohamad, S Floriot, L Henry, T Tozzi, G Jiang, T Wurtz, O Lefebvre, A Shugay, M Tong, J Vaudry, D Arkle, S doRego, JC Górecki, DC
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Peltz, Gary UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	1 January 2015
Date Type:	Publication
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title:	PLoS Medicine
Volume:	12
Number:	10
DOI or Unique Handle:	10.1371/journal.pmed.1001888
Institution:	University of Pittsburgh
Schools and Programs:	School of Medicine > Immunology School of Medicine > Medicine School of Medicine > Surgery Swanson School of Engineering > Bioengineering
Refereed:	Yes
ISSN:	1549-1277
Date Deposited:	25 Jul 2016 17:12
Last Modified:	30 Mar 2021 15:55
URI:	http://d-scholarship.pitt.edu/id/eprint/28579

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