383. Clinico-Pathological Correlation in the Earliest Stages of Muscular Dystrophy Suggests Sensitive Physiological Parameters as Novel Primary Endpoints for Systemic Gene Therapy

Abstract

The clinical progression of Duchenne Muscular Dystrophy (DMD) begins with locomotive symptoms in childhood but eventually includes symptoms of severe cardiorespiratory failure. Our studies in mdx mice and GRMD dogs have reavealed surprisingly large early deficits in physiological reserve, attributable to the deficiency of dystrophin. In young GRMD dogs, the findings of diaphragmatic fibrosis and myofiber shortening correlated strongly with non-invasively measured abnormalities in respiratory muscle recruitment. In juvenile GRMD dogs without clinical signs of heart failure, detailed studies of cardiac mechanics revealed profoundly abnormal Frank-Starling and inotropic responses. Thus, submaximal exercise loading has the capactiy to reveal very early, otherwise subclinical deficits in physiological reserve. We have utilized several non-invasive systems to measure integrative cardiopulmonary mechanics in animals trained to undertake submaximal volitional exercise. Our findings demonstrate the possibility of continuous non-invasive monitoring of cardiac output, stroke volume, systemic vascular resistance, and several ventilatory parameters in young dogs and children during treadmill exercise, as well as upright and recumbent bicycling at work outputs appropriate for low risk serial testing in the earliest stages of DMD. As the field contemplates primary endpoints for use in trials of systemic gene therapy, these metrics hold promise as the most sensitive measurements of the earliest functional deficits in organ systems eventually responsible for the lethality of DMD.