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.

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Citation

Published Version (Please cite this version)

10.1016/j.ymgme.2011.02.006

Publication Info

Koeberl, Dwight D, Xiaoyan Luo, Baodong Sun, Alison McVie-Wylie, Jian Dai, Songtao Li, Suhrad G Banugaria, Y-T Chen, et al. (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.

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Scholars@Duke

Koeberl

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. 

Sun

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 studies include protein/enzyme therapy, AAV-mediated gene therapy, and substrate reduction therapy with small molecule drugs.

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 identification of novel genes associated with the human disease. Genetic markers associated with drug-induced Stevens-Johnson syndrome and other adverse drug reactions have been identified. Prospective studies are in progress to assess the utilization of these markers to prevent the adverse drug reactions. A systematic, genome-wide, phenotype-driven mutagenesis program for gene function studies in the mouse have resulted in the identification of several mouse models of human genetic metabolic diseases. We will continue our research along these lines to identify more novel disease genes/ targets and to increase our understanding of the diseases.

2). Genetics and molecular mechanisms of Stevens-Johnson syndrome. With the identification of HLA-B allele strongly linked to the genetic susceptibility to the drug-induced Stevens-Johnson syndrome, we are investigating how the specific HLA allele mediated the cell toxicity in causing disseminated keratinocyte death.

3). Functional characterization of a novel glucose transporter and its role in diabetes mellitus. We cloned a novel glucose transporter (Glu 10), which is highly expressed in pancreas and liver and is located on a region of a chromosome where a diabetes mellitus type II locus has been mapped. We are currently investigating its role in diabetes by studying mouse models carrying the GLU10 mutations and by direct genetic association study of human patients affected with diabetes.

4). Enzyme and gene therapy and targeting mechanisms of Pompe disease.
Pompe disease is a fatal genetic muscle disorder. As enzyme replacement therapy for Pompe disease moves into clinical reality the fundamental question of how the enzyme targets the heart and skeletal muscle and why some patients respond better than others remain unanswered. We have generated tissue-specific MPR300 knockout mouse model and other animal models to help answer these questions.


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