Project Description: Skeletal muscle is essential for mobility and its health relies upon innervation. Accidental limb trauma with peripheral nerve injury results in immediate loss of muscle function and wasting. This is reversible if re-innervation occurs in a timely manner, due to muscle’s robust capacity for regeneration and self-repair. If re-innervation is delayed however, regeneration/repair is exhausted and muscle fibroses. Peripheral nerves possess the innate ability to regenerate; but the rate is limited to 1 mm/day. Thus, with proximal limb trauma (e.g. above the elbow), by the time the nerve regrows to its target muscles (e.g. hand), muscles restorative potential is lost. Permanent physical disability results, negatively impacting quality of life and inducing significant societal costs (e.g. health care, lost productivity/job retraining, long term disability).
We have no therapies to sustain denervated muscle awaiting re-innervation. We aim to use the novel approach of ultrasound mediated gene delivery (UMGD) to promote the repair and regeneration of denervated muscle and sustain its receptivity to reinnervation. With UMGD, genes in minicircle plasmids coupled to carrier microbubbles are systemically administered, and directed to induce tissue specific transfection and temporary (6-8 week) gene expression by high-power ultrasound mediated microbubble destruction over the target tissue. Using the rodent tibial nerve transection model, we will provide tailored non-invasive, localized, sequential gene therapy to denervated muscle to sustain its reparative capacity thereby enabling complete functional recovery with re-innervation. As therapeutic ultrasound and microbubbles are already in use for clinical sonothrombolysis, this is a project of rapid and highly translatable potential.