Cardiac Remodeling After Enzyme Replacement Therapy with Acid α-Glucosidase for Infants with Pompe Disease
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Infantile Pompe disease (glycogen storage disease type 2) is a fatal disorder caused by deficiency of acid α-glucosidase. This deficiency results in glycogen accumulation in the lysosomes of many tissues including cardiac muscle. The disease is characterized by profound hypotonia, poor growth, organomegaly, and cardiomegaly. Severe hypertrophic cardiomyopathy often is present in early infancy, and most patients die of cardiac or respiratory failure in the first year of life. This report describes the cardiac response of infants with Pompe disease to a phase 2 trial of enzyme replacement therapy (ERT).
Eight patients with classical infantile Pompe disease were given intravenous recombinant human GAA (rhGAA) for 1 year. Cardiac monitoring included echocardiography, electrocardiograms (ECGs), chest radiographs, and clinical cardiac evaluation at 4, 8, 12, 24, 36, and 52 weeks. At 52 weeks, 6 patients were alive.
Most of the treated patients had rapid regression of ventricular hypertrophy in response to ERT, with near normalization of posterior wall thickness, ventricular mass, and ventricular size. Systolic ventricular function was preserved despite rapid changes in ventricular mass and size. Concomitantly, ECGs documented lengthening of the PR interval and decreased ventricular voltages, whereas chest radiographs documented a decreased cardiothoracic ratio. Symptoms of pulmonary congestion were diminished, and survival was improved.
The cardiovascular system responds quickly and strikingly to ERT with rhGAA, suggesting rapid reversal of excessive glycogen storage in cardiac muscle cells. Changes in ventricular mass and function are maintained throughout 1 year of follow-up evaluation and associated with decreased morbidity and prolonged survival.
KeywordsHypertrophy Cardiomyopathy Pediatrics Genetics Trials
We thank the study patients and their families for their participation in this clinical trial. In addition, we mention our great appreciation for the support and expertise of the physicians, study coordinators, and research assistants, without whom this study could not have been conducted. Finally, we acknowledge the tremendous input of the following individuals from the Genzyme Corporation, without whom this trial could not have been completed: Jennifer Hunt, Tara O’Meara, Florence Yong, MS PhD, and Deyanira Corzo, MD. This trial was supported by a grant from the Genzyme Corporation to the various sites at which patients were treated. Priya S. Kishnani and Y. T. Chen received research and grant support from the Genzyme Corp. Priya S. Kishnani is a member of the Pompe Disease Advisory Board for the Genzyme Corporation. Jami C. Levine and Y. T. Chen have served as consultants for the Genzyme Corporation. The U.S. FDA and the European Union have approved rhGAA, in the form of Genzyme’s product, Myozyme, as therapy for Pompe disease. Duke University and the inventors for the method of treatment and the predecessors of the cell lines used to generate the enzyme used in this clinical trial may benefit financially pursuant to the Duke University’s Policy on Inventions, Patents, and Technology Transfer. This study was supported in part by grants M01-RR30 and M01-RR01271 from the General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health and by Genzyme Corporation.
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