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Bettica, P. I worked with veterinary pathologists and neurologists to identify multiple lines of cats and dogs showing loss of dystrophin in skeletal muscle—for example, animal models of DMD [ 31 , 32 , 33 , 34 ]. Importantly, vamorolone appears to show fewer of the severe safety concerns typically observed with chronic corticosteroid treatment.
For all DMD experimental therapeutic approaches, the target tissue of the drug or intervention is skeletal muscle and constituent myofibers. But in DMD patients, many specific muscles show an early progression to fibrofatty replacement—the myofiber target tissue may no longer be available to the drug to exert potential benefit.
This model also predicts that efficacious therapies likely need to target multiple pathways, including inflammation, mitochondrial function, and fibrosis and failed regeneration. Indeed, all dystrophin replacement clinical trials still require commensurate corticosteroid treatment to mitigate effects of inflammation despite the severe side effects associated with these drugs.
Looking forward, the enormous DMD gene and enigmatic dystrophin protein will continue to present us with challenges in our efforts to understand the biology, and aid patients via therapeutics. We understand the gene mutations, the effects on dystrophin, and many features of the biochemical role of dystrophin in muscle. Indeed, the identification of the dystrophin gene and protein heralded the era of human disease genomics that has dramatically increased our understanding of human genetic disease.
However, we do not understand the downstream consequences of dystrophin deficiency in a cell and its surrounding tissue. Why is the heart relatively spared until quite late in the disease process? DMD therapeutics may require multidrug regimens, yet such multidrug approaches pose challenges with regard to both pharmaceutical development and regulatory pathways.
The author thanks Louis Kunkel for serving as an outstanding mentor and for the opportunity to join his laboratory. National Center for Biotechnology Information , U. The Febs Journal. FEBS J. Published online Jul Eric P. Hoffman 1. Author information Article notes Copyright and License information Disclaimer. Hoffman, Email: ude. Corresponding author. Received Jun 12; Accepted Jun This article has been cited by other articles in PMC.
Abstract Duchenne muscular dystrophy is the most common neuromuscular genetic disorder. Keywords: Duchenne muscular dystrophy, dystrophin, membrane cytoskeleton, skeletal muscle. Open in a separate window. The transition to therapy The identification of the DMD gene and dystrophin protein led to hopes for new therapeutic approaches that addressed the primary defect.
Becker muscular dystrophy I think the discoveries regarding the clinically milder Becker muscular dystrophy BMD have been illuminating at multiple levels. Summary Looking forward, the enormous DMD gene and enigmatic dystrophin protein will continue to present us with challenges in our efforts to understand the biology, and aid patients via therapeutics. Acknowledgements The author thanks Louis Kunkel for serving as an outstanding mentor and for the opportunity to join his laboratory.
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What is the status of DMD research? Parsippany, NJ. Ryder, S. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: An evidence review. Orphanet Journal of Rare Diseases Pediatrics Looking for more information, support or ways to get involved?
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