Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy

TL;DR

A new synthetic polymer prevents muscle damage in Duchenne muscular dystrophy, a fatal muscle disease, by stabilizing cell membranes.

Contribution

A bottlebrush block copolymer is shown to be vastly more effective than linear polymers in preventing DMD-related muscle damage.

Findings

The BB polymer is ~150,000 times more potent than linear polymers in restoring muscle function in vitro.

In vivo delivery of the BB polymer prevents skeletal and diaphragm muscle damage in DMD animals.

The polymer also blocks stress-induced cardiac injury and death in DMD models.

Abstract

Advances in synthetic chemistry have led to an exciting class of polymers with an enormous range of molecular architectures featuring highly branched “bottlebrush” designs. A bottlebrush block copolymer (BB polymer) is identified here as a membrane stabilizer for the inherited muscle disease, Duchenne muscular dystrophy (DMD). Remarkably, this BB polymer is shown to be ~150,000 times more potent than the most effective linear triblock/diblock polymer membrane stabilizers. Furthermore, strikingly, delivery of the BB polymer in vivo is sufficient to prevent the onset of muscle damage and membrane leakiness in DMD animals. These findings reveal a connection between the branched molecular architecture in the mildly amphiphilic synthetic polymer and physiological action linked to interactions with lipid bilayers.

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.

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