Sang-Oh Han1, Alexina C Haynes2, Songtao Li1, Dennis M Abraham3, Priya S Kishnani4, Richard Steet5, Dwight D Koeberl6. 1. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States of America. 2. Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States of America. 3. Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States of America. 4. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States of America; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States of America. 5. Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States of America; Greenwood Genetic Center, Greenwood, SC, United States of America. 6. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States of America; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States of America. Electronic address: dwight.koeberl@duke.edu.
Abstract
Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA) leading to progressive myopathy. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA has limitations, including inefficient uptake of rhGAA in skeletal muscle linked to low cation-independent mannose-6-phosphate receptor (CI-MPR) expression. PURPOSE: To test the hypothesis that antihypertensive agents causing muscle hypertrophy by increasing insulin-like growth factor 1 expression can increase CI-MPR-mediated uptake of recombinant enzyme with therapeutic effects in skeletal muscle. METHODS: Three such agents were evaluated in mice with Pompe disease (carvedilol, losartan, and propranolol), either with or without concurrent ERT. RESULTS: Carvedilol, a selective β-blocker, increased muscle strength but reduced biochemical correction from ERT. Administration of drugs alone had minimal effect, with the exception of losartan that increased glycogen storage and mortality either by itself or in combination with ERT. CONCLUSION: The β-blocker carvedilol had beneficial effects during ERT in mice with Pompe disease, in comparison with propranolol or losartan. Caution is warranted when prescribing antihypertensive drugs in Pompe disease.
Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA) leading to progressive myopathy. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA has limitations, including inefficient uptake of rhGAA in skeletal muscle linked to low cation-independent mannose-6-phosphate receptor (CI-MPR) expression. PURPOSE: To test the hypothesis that antihypertensive agents causing muscle hypertrophy by increasing insulin-like growth factor 1 expression can increase CI-MPR-mediated uptake of recombinant enzyme with therapeutic effects in skeletal muscle. METHODS: Three such agents were evaluated in mice with Pompe disease (carvedilol, losartan, and propranolol), either with or without concurrent ERT. RESULTS:Carvedilol, a selective β-blocker, increased muscle strength but reduced biochemical correction from ERT. Administration of drugs alone had minimal effect, with the exception of losartan that increased glycogen storage and mortality either by itself or in combination with ERT. CONCLUSION: The β-blocker carvedilol had beneficial effects during ERT in mice with Pompe disease, in comparison with propranolol or losartan. Caution is warranted when prescribing antihypertensive drugs in Pompe disease.
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