Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.
Abstract
Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for
Pompe disease; however, the response of skeletal muscle, as opposed to the heart,
has been attenuated. The poor response of skeletal muscle has been attributed to the
low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal
muscle compared to heart. To further understand the role of CI-MPR in Pompe disease,
muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe
disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating
ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized
by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction
of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with
the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective
β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased
efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to
enzyme replacement therapy in Pompe disease. Biochemical correction improved in both
muscle and non-muscle tissues, indicating that therapy could be similarly enhanced
in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might
improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing
receptor-mediated uptake of GAA.
Type
Journal articleSubject
Adrenergic beta-AgonistsAnimals
Clenbuterol
Disease Models, Animal
Enzyme Replacement Therapy
Glycogen
Glycogen Storage Disease Type II
Male
Mice
Mice, Knockout
Motor Activity
Muscle, Skeletal
Receptor, IGF Type 2
alpha-Glucosidases
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https://hdl.handle.net/10161/15090Published Version (Please cite this version)
10.1016/j.ymgme.2011.02.006Publication Info
Koeberl, Dwight D; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li,
Songtao; ... Bali, Deeksha S (2011). Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate
receptor expression in skeletal muscle. Mol Genet Metab, 103(2). pp. 107-112. 10.1016/j.ymgme.2011.02.006. Retrieved from https://hdl.handle.net/10161/15090.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.
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Show full item recordScholars@Duke
Deeksha Sarihyan Bali
Professor of Pediatrics
1)Development of new non-invasive laboratory diagnostic methods using enzymology and
molecular diagnostic techniques for Glycogen Storage Diseases (GSDs) and Lysosomal
Storage Diseases (LSDs) like Pompe, Fabry, Gaucher, MPS - for early diagnosis and
treatment modalities. Exploration of new high throughput diagnostic platforms with
an idea of implementation into New born screening (NBS)of these diseases. 2)Clinical
research studies associated with Pompe disease with a goal to improve
Yuan-Tsong Chen
Professor Emeritus of Pediatrics
Our overall research interests are in translational research. We aim at translating
the promise of genomic medicine into clinical reality. Specific projects at present
time include: 1). Identification of novel genes/targets associated with human diseases.
This includes susceptibility genes for common multi-factorial diseases and adverse
drug reactions. Genetic epidemiology, mouse ENU mutagenesis, bioinformatics and proteomics
are some approaches that we use in identific
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
Baodong Sun
Associate Professor in Pediatrics
My overall research interests are finding effective treatment for human glycogen storage
diseases (GSDs) and other inherited metabolic disorders. My current research focuses
on identification of novel therapeutic targets and development of effective therapies
for GSD II (Pompe disease), GSD III (Cori disease), and GSD IV (Andersen disease)
using cellular and animal disease models. The main therapeutic approaches we are using
in our pre-clinical studie
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