Title |
Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase
|
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Published in |
Science Translational Medicine, November 2017
|
DOI | 10.1126/scitranslmed.aam6375 |
Pubmed ID | |
Authors |
Francesco Puzzo, Pasqualina Colella, Maria G Biferi, Deeksha Bali, Nicole K Paulk, Patrice Vidal, Fanny Collaud, Marcelo Simon-Sola, Severine Charles, Romain Hardet, Christian Leborgne, Amine Meliani, Mathilde Cohen-Tannoudji, Stephanie Astord, Bernard Gjata, Pauline Sellier, Laetitia van Wittenberghe, Alban Vignaud, Florence Boisgerault, Martine Barkats, Pascal Laforet, Mark A Kay, Dwight D Koeberl, Giuseppe Ronzitti, Federico Mingozzi |
Abstract |
Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa-/-) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa-/- mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector-mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 24 | 30% |
France | 7 | 9% |
United Kingdom | 5 | 6% |
Argentina | 2 | 2% |
Russia | 1 | 1% |
Colombia | 1 | 1% |
Brazil | 1 | 1% |
Finland | 1 | 1% |
Spain | 1 | 1% |
Other | 4 | 5% |
Unknown | 34 | 42% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 49 | 60% |
Scientists | 22 | 27% |
Science communicators (journalists, bloggers, editors) | 6 | 7% |
Practitioners (doctors, other healthcare professionals) | 4 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 149 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 31 | 21% |
Student > Ph. D. Student | 23 | 15% |
Student > Master | 16 | 11% |
Student > Bachelor | 14 | 9% |
Student > Doctoral Student | 5 | 3% |
Other | 18 | 12% |
Unknown | 42 | 28% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 41 | 28% |
Agricultural and Biological Sciences | 26 | 17% |
Medicine and Dentistry | 14 | 9% |
Neuroscience | 5 | 3% |
Immunology and Microbiology | 4 | 3% |
Other | 12 | 8% |
Unknown | 47 | 32% |