Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with 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.


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.


Three such agents were evaluated in mice with Pompe disease (carvedilol, losartan, and propranolol), either with or without concurrent ERT.


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.


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.





Published Version (Please cite this version)


Publication Info

Han, Sang-Oh, Alexina C Haynes, Songtao Li, Dennis M Abraham, Priya S Kishnani, Richard Steet and Dwight D Koeberl (2020). Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with Pompe disease. Molecular genetics and metabolism, 129(2). pp. 73–79. 10.1016/j.ymgme.2019.10.005 Retrieved from https://hdl.handle.net/10161/26521.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.



Dennis M Abraham

Assistant Professor of Medicine

Dwight D. Koeberl

Professor of Pediatrics

As a physician-scientist practicing clinical and biochemical genetics, I am highly motivated to seek improved therapy for my patients with inherited disorders of metabolism. The focus of our research has been the development of gene therapy with adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 
1) GSD Ia: Glucose-6-phosphatase (G6Pase) deficient animals provide models for developing new therapy for GSD Ia, although early mortality complicates research with both the murine and canine models of GSD Ia. We have prolonged the survival and reversed the biochemical abnormalities in G6Pase-knockout mice and dogs with GSD type Ia, following the administration of AAV8-pseudotyped AAV vectors encoding human G6Pase. More recently, we have performed genome editing to integrate a therapeutic transgene in a safe harbor locus for mice with GSD Ia, permanently correcting G6Pase deficiency in the GSD Ia liver. Finally, we have identified reduced autophagy as an underlying hepatocellular defect that might be treated with pro-autophagic drugs in GSD Ia.
2) GSD II/Pompe disease: Pompe disease is caused by the deficiency of acid-alpha-glucosidase (GAA) in muscle, resulting in the massive accumulation of lysosomal glycogen in striated muscle with accompanying weakness. While enzyme replacement has shown promise in infantile-onset Pompe disease patients, no curative therapy is available. We demonstrated that AAV vector-mediated gene therapy will likely overcome limitations of enzyme replacement therapy, including formation of anti-GAA antibodies and the need for frequent infusions. We demonstrated that liver-restricted expression with an AAV vector prevented antibody responses in GAA-knockout mice by inducing immune tolerance to human GAA. Antibody responses have complicated enzyme replacement therapy for Pompe disease and emphasized a potential advantage of gene therapy for this disorder. The strategy of administering low-dose gene therapy prior to initiation of enzyme replacement therapy, termed immunomodulatory gene therapy, prevented antibody formation and increased efficacy in Pompe disease mice. We are currently conducting a Phase I clinical trial of immunomodulatory gene therapy in adult patients with Pompe disease. Furthermore, we have developed drug therapy to increase the receptor-mediated uptake of GAA in muscle cells, which provides adjunctive therapy to more definitively treat Pompe disease.
3) PKU: In collaboration with researchers at OHSU, we performed an early gene therapy experiment that demonstrated long-term biochemical correction of PKU in mice with an AAV8 vector. PKU is a very significant disorder detected by newborn screening and currently inadequately treated by dietary therapy. Phenylalanine levels in mice were corrected in the blood, and elevated phenylalanine causes mental retardation and birth defects in children born to affected women, and gene therapy for PKU would address an unmet need for therapy in this disorder.

Currently we are developing methods for genome editing that will stably correct the enzyme  deficiency in GSD Ia and in Pompe disease.  Our long-term goal is to develop efficacious genome editing for glycogen storage diseases, which will allow us to treat these conditions early in life with long-term benefits. 

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.