Structure-Function of Synthetic Membrane-Sealant Copolymers for Dystrophic Muscle

Abstract

Muscle membrane vulnerability is a hallmark of Duchenne Muscular Dystrophy (DMD), an X-linked neuromuscular disease that results in progressive skeletal muscle weakness and significant cardiomyopathy. We propose the use of membrane-sealant copolymers as an innovative and unique potential therapeutic for DMD. The tri-block copolymer family comprises molecules made of a hydrophobic polypropylene oxide (PPO) core flanked bilaterally by linear chains of hydrophilic polyethylene oxide (PEO) chemical moieties. Block copolymers exist at various molecular weights and PPO/PEO ratios and it is currently not known what structural properties confer membrane sealing capacity to copolymers of this family. We and other groups have shown that one such sealant, poloxamer P188, protects dystrophic hearts in vitro and in vivo in both small and large animal models of DMD but its apparent efficacy is significantly reduced in skeletal muscle in vivo. This underscores the importance of discovering more potent membrane sealants to treat all striated muscles in DMD. We have initiated a collaborative structure-function approach by implementing and refining an in vitro membrane injuring osmotic and shear stress assay to analyze the membrane sealing functions of these tri-block copolymer family members on dystrophic skeletal muscle to systematically determine the effects of PPO/PEO ratio and molecular weight on membrane protection. We will present progress on copolymer structure-function understanding and discuss how these new data will shed light into the structural requisite for more efficacious and potent membrane sealants.