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Published on: December 20, 2017
Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated
Baodong Sun1, Haoyue Zhang, Andrew Bird
1Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Insights
Gene therapy for Pompe disease shows promise but is less effective in older mice. Early treatment with adeno-associated virus (AAV) vectors is crucial for optimal outcomes in this rare genetic disorder.
Area of Science:
- Genetics and Genetic Diseases
- Molecular and Cellular Biology
- Biomedical Engineering
Background:
- Infantile-onset glycogen storage disease type II (Pompe disease) is fatal in early childhood without treatment.
- Late-onset Pompe disease leads to progressive skeletal muscle weakness.
- Adeno-associated virus (AAV) vector-mediated gene therapy offers a potential alternative to enzyme replacement therapy.
Purpose of the Study:
- To evaluate the efficacy of AAV gene therapy in advanced-stage Pompe disease mouse models.
- To compare the effectiveness of liver-specific versus muscle-specific AAV vectors.
- To identify factors influencing therapeutic outcomes in older Pompe disease mice.
Main Methods:
- Administration of liver-specific or muscle-specific AAV vectors to 12- and 17-month-old Pompe disease mice.
- Biochemical assessment of acid alpha-glucosidase (GAA) activity and glycogen levels in cardiac and skeletal muscle.
- Evaluation of Rotarod performance, Western blotting, and urinary biomarkers post-vector administration.
Main Results:
- A liver-specific AAV vector successfully corrected glycogen storage in the heart and diaphragm, improving motor function.
- Skeletal muscle glycogen clearance was less efficient in older mice compared to younger ones.
- A muscle-specific AAV vector showed high skeletal muscle transduction but incomplete glycogen clearance; reduced cardiac and liver transduction in older, especially female, mice impacted overall efficacy.
Conclusions:
- Adeno-associated virus (AAV) vector-mediated gene therapy efficacy is diminished in advanced Pompe disease mouse models.
- Early intervention is essential to achieve maximal therapeutic benefits from gene therapy for Pompe disease.
Background:
Infantile-onset glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) causes death early in childhood from cardiorespiratory failure in the absence of effective treatment, whereas late-onset Pompe disease causes a progressive skeletal myopathy. The limitations of enzyme replacement therapy could potentially be addressed with adeno-associated virus (AAV) vector-mediated gene therapy.
Methods:
AAV vectors containing tissue-specific regulatory cassettes, either liver-specific or muscle-specific, were administered to 12- and 17-month-old Pompe disease mice to evaluate the efficacy of gene therapy in advanced Pompe disease. Biochemical correction was evaluated through acid alpha-glucosidase (GAA) activity and glycogen content analyses of the heart and skeletal muscle. Western blotting, urinary biomarker, and Rotarod performance were evaluated after vector administration.
Results:
The AAV vector containing the liver-specific regulatory cassette secreted high-level human GAA into the blood and corrected glycogen storage in the heart and diaphragm. The biochemical correction of the heart and diaphragm was associated with efficacy, as reflected by increased Rotarod performance; however, the clearance of glycogen from skeletal muscles was relatively impaired compared to in younger Pompe disease mice. An alternative vector containing a muscle-specific regulatory cassette transduced skeletal muscle with high efficiency, but also failed to achieve complete clearance of accumulated glycogen. Decreased transduction of the heart and liver in older mice, especially in females, was implicated as a cause for reduced efficacy in advanced Pompe disease.
Conclusions:
The impaired efficacy of AAV vector-mediated gene therapy in old Pompe disease mice emphasizes the need for early treatment to achieve full efficacy.
