Chemical-based membrane sealants for dystrophic muscle

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DESCRIPTION (provided by applicant): The long-range goal of this research is to design, test, and implement a new chemical-based membrane repair therapy to halt, prevent and possibly reverse the marked striated muscle deterioration in Duchenne muscular dystrophy (DMD). Most DMD patients have a pronounced cardiomyopathy by the second decade of life, with heart failure accounting for at least 15-30% of deaths in DMD. This proposal has marked health relevance as it seeks a new therapeutic strategy featuring systemic delivery of chemical-based membrane sealant poloxamers to protect striated muscles in dystrophic dogs and mice. Recent work demonstrates the acute protective effects of poloxamer 188 (P188) on cardiac myocyte and whole heart function in the mdx mouse model of DMD. Compared with the mdx mouse, the dystrophic dog displays overt striated muscle disease that parallels closely in both timing and severity the progression of the dystrophic symptoms of the human patients. P188 has been shown to be safe and well tolerated in rodents, dogs, and humans. The working hypotheses guiding this proposal are: 1) cellular dysfunction will be greater in cardiac and skeletal muscle from dystrophic dogs compared to dystrophic mice, 2) acute treatment with P188 to isolated striated muscle of dystrophic dogs will have greater beneficial effects as compared to mdx mice; and 3) chronically administered P188 will produce long-term benefits to striated muscle structure and function in both mouse and dog models of DMD. This proposal is uniquely positioned to determine the mechanism of action and therapeutic potential of P188 in animal models of DMD. In vitro studies will utilize a unique micro-carbon fiber contractile assay to directly determine single myocyte passive and active forces under physiological load. In vivo acute and chronic studies will determine the efficacy of P188 infusion in vivo in small and large mammalian models of DMD. The Specific Aims are: Aim 1. To compare the effects of P188 on passive and active contractile performance in membrane intact single cardiac myocytes and in skeletal muscles isolated from dystrophin-deficient mice and dogs. Hypothesis: Acute exposure to P188 will immediately correct deficits in passive tension-extension properties and active isometric force with the magnitude of restitution significantly greater in canine than in mouse cardiac myocytes. P188 treatment will protect intact skeletal muscle of dystrophic mice contraction-induced injury. Aim 2: To test whether systemic delivery of P188 will halt, prevent or reverse the myocardial dysfunction and failure in dystrophin-deficient mice and dogs in vivo. Hypothesis: Infusion of P188 will confer both immediate and long-term beneficial effects to myocardial performance in vivo with the effects being comparatively greater in dystrophin-deficient dogs than in mice.