Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle
Dwight D Koeberl, Xiaoyan Luo, Baodong Sun, Alison McVie-Wylie, Jian Dai, Songtao Li, Suhrad G Banugaria, Y-T Chen, Deeksha S Bali, Dwight D Koeberl, Xiaoyan Luo, Baodong Sun, Alison McVie-Wylie, Jian Dai, Songtao Li, Suhrad G Banugaria, Y-T Chen, Deeksha S Bali
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.
Conflict of interest statement
Conflict of interest: YT, DB and DDK have received research/grant support from Genzyme Corporation in the past. rhGAA, in the form of Genzyme’s product, Myozyme™ and Lumizyme™ is now approved by the US FDA and the European Union as therapy for Pompe disease. Duke University and inventors for the method of treatment and predecessors of the cell lines used to generate the enzyme (rhGAA) used in various clinical trials will receive royalty payments pursuant to the University’s Policy on Inventions, Patents and Technology. AMW is currently employed by Genzyme Corporation.
Copyright © 2011 Elsevier Inc. All rights reserved.
Figures
![Fig. 1. Impaired rhGAA uptake in DKO…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3101281/bin/nihms281944f1.jpg)
![Fig. 2. Western blot analysis of CI-MPR…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3101281/bin/nihms281944f2.jpg)
![Fig. 3. Enhanced Rotarod performance and weight…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3101281/bin/nihms281944f3.jpg)
![Fig. 4. Enhanced efficacy from ERT plus…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3101281/bin/nihms281944f4.jpg)
![Fig. 5. Decreased glycogen accumulation in skeletal…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3101281/bin/nihms281944f5.jpg)
![Fig. 6. Western blot analysis of CI-MPR…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3101281/bin/nihms281944f6.jpg)
Source: PubMed