Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy
Abstract
Duchenne muscular dystrophy (DMD) is a fatal genetic disease of progressive muscle deterioration with no cure. DMD treatment requires a body-wide approach to target all diseased striated muscles: limb, respiratory, and heart. To address this, we focus studies on blocking the onset of muscle membrane instability, the primary defect in DMD, as a promising yet unmet druggable target. Here, data show the remarkable potency of a synthetic poly(ethylene oxide)/poly(propylene oxide) side chain–based bottlebrush block copolymer, ~150,000 times more potent than linear polymers, to rapidly restore contractile function to DMD skeletal muscle fibers in vitro. Strikingly, upon bottlebrush polymer delivery to DMD animals, results show highly efficacious prevention of the onset of skeletal and diaphragm muscle damage and the blocking of stress-induced cardiac injury and death in vivo. These data suggest bottlebrush polymers as a potent stand-alone muscle membrane-stabilizing therapeutic for DMD. Given DMD’s early childhood onset, together with newborn screening for DMD, bottlebrush macromolecules could be envisioned as an early therapy to preserve and protect viable muscle and potentially for other acquired or inherited diseases involving membrane damage.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Houda Cohen
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Addeli Bez Batti Angulski
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Joseph D. Quick
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Taylor S. Kuebler
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Brian R. Thompson
Department of Integrative Biology and Physiology, University of Minnesota Medical School
John Bauer
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Dongwoo Hahn
Department of Integrative Biology and Physiology, University of Minnesota Medical School
DeWayne Townsend
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Joseph F. Hassler
Department of Chemical Engineering and Materials Science, University of Minnesota
Benjamin J. Hackel
Department of Chemical Engineering and Materials Science, University of Minnesota
Timothy P. Lodge
Department of Chemical Engineering and Materials Science, University of Minnesota
Yuk Y. Sham
Department of Integrative Biology and Physiology, University of Minnesota Medical School
Frank S. Bates
Department of Chemical Engineering and Materials Science, University of Minnesota
Joseph M. Metzger
Department of Integrative Biology and Physiology, University of Minnesota Medical School