Abstract:
:Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration. A unique therapeutic approach for DMD is the use of synthetic membrane stabilizers to protect the fragile dystrophic sarcolemma against contraction-induced mechanical stress. Block copolymer-based membrane stabilizer poloxamer 188 (P188) has been shown to protect the dystrophic myocardium. In comparison, the ability of synthetic membrane stabilizers to protect fragile DMD skeletal muscles has been less clear. Because cardiac and skeletal muscles have distinct structural and functional features, including differences in the mechanism of activation, variance in sarcolemma phospholipid composition, and differences in the magnitude and types of forces generated, we speculated that optimized membrane stabilization could be inherently different. Our objective here is to use principles of pharmacodynamics to evaluate membrane stabilization therapy for DMD skeletal muscles. Results show a dramatic differential effect of membrane stabilization by optimization of pharmacodynamic-guided route of poloxamer delivery. Data show that subcutaneous P188 delivery, but not intravascular or intraperitoneal routes, conferred significant protection to dystrophic limb skeletal muscles undergoing mechanical stress in vivo. In addition, structure-function examination of synthetic membrane stabilizers further underscores the importance of copolymer composition, molecular weight, and dosage in optimization of poloxamer pharmacodynamics in vivo.
journal_name
Mol Ther Methods Clin Devjournal_title
Molecular therapy. Methods & clinical developmentauthors
Houang EM,Haman KJ,Filareto A,Perlingeiro RC,Bates FS,Lowe DA,Metzger JMdoi
10.1038/mtm.2015.42subject
Has Abstractpub_date
2015-11-11 00:00:00pages
15042issn
2329-0501pii
S2329-0501(16)30054-7journal_volume
2pub_type
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