Improved efficacy of a next-generation ERT in murine Pompe disease
| Autor: | Yi Lun, Anju Nair, Anadina Garcia, Jessie Feng, Kenneth J. Valenzano, Tuske Steven, Rosa Puertollano, Richie Khanna, Michelle Frascella, Su Xu, Russell Gotschall, Jose A. Martina, Maria Cecilia Della Valle, Evelyn Ralston, Adriane Schilling, Hung V. Do, Nina Raben, Abdul S. Ponery, Rebecca Soska |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine 1-Deoxynojirimycin Disease Pharmacology Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Miglustat medicine Animals Humans Enzyme Replacement Therapy Investigational therapy Muscle Skeletal Alglucosidase alfa Mice Knockout Mannosephosphates Glycogen Storage Disease Type II business.industry Autophagy alpha-Glucosidases General Medicine Enzyme replacement therapy Rats Pharmacological chaperone Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Female Lysosomes business Glycogen Research Article medicine.drug |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.125358 |
| Popis: | Pompe disease is a rare inherited disorder of lysosomal glycogen metabolism due to acid α-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA (rhGAA), is the only approved treatment for Pompe disease. Although alglucosidase alfa has provided clinical benefits, its poor targeting to key disease-relevant skeletal muscles results in suboptimal efficacy. We are developing an rhGAA, ATB200 (Amicus proprietary rhGAA), with high levels of mannose-6-phosphate that are required for efficient cellular uptake and lysosomal trafficking. When administered in combination with the pharmacological chaperone AT2221 (miglustat), which stabilizes the enzyme and improves its pharmacokinetic properties, ATB200/AT2221 was substantially more potent than alglucosidase alfa in a mouse model of Pompe disease. The new investigational therapy is more effective at reversing the primary abnormality — intralysosomal glycogen accumulation — in multiple muscles. Furthermore, unlike the current standard of care, ATB200/AT2221 dramatically reduces autophagic buildup, a major secondary defect in the diseased muscles. The reversal of lysosomal and autophagic pathologies leads to improved muscle function. These data demonstrate the superiority of ATB200/AT2221 over the currently approved ERT in the murine model. |
| Databáze: | OpenAIRE |
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