Improved efficacy of a next-generation ERT in murine Pompe disease
Su Xu, Yi Lun, Michelle Frascella, Anadina Garcia, Rebecca Soska, Anju Nair, Abdul S. Ponery, Adriane Schilling, Jessie Feng, Steven Tuske, Maria Cecilia Della Valle, José A. Martina, Evelyn Ralston, Russell Gotschall, Kenneth J. Valenzano, Rosa Puertollano, Hung V. Do, Nina Raben, Richie Khanna
Su Xu, Yi Lun, Michelle Frascella, Anadina Garcia, Rebecca Soska, Anju Nair, Abdul S. Ponery, Adriane Schilling, Jessie Feng, Steven Tuske, Maria Cecilia Della Valle, José A. Martina, Evelyn Ralston, Russell Gotschall, Kenneth J. Valenzano, Rosa Puertollano, Hung V. Do, Nina Raben, Richie Khanna
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Research Article Genetics Therapeutics

Improved efficacy of a next-generation ERT in murine Pompe disease

Abstract

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.

Authors

Su Xu, Yi Lun, Michelle Frascella, Anadina Garcia, Rebecca Soska, Anju Nair, Abdul S. Ponery, Adriane Schilling, Jessie Feng, Steven Tuske, Maria Cecilia Della Valle, José A. Martina, Evelyn Ralston, Russell Gotschall, Kenneth J. Valenzano, Rosa Puertollano, Hung V. Do, Nina Raben, Richie Khanna

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Figure 6

Second harmonic generation (SHG) and 2PEF imaging show improvement in fibers from ATB200/AT2221–treated Gaa-KO mice.

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Second harmonic generation (SHG) and 2PEF imaging show improvement in fi...
Sixteen-week-old male Gaa-KO mice received 4 biweekly administrations of vehicle, alglucosidase alfa, or ATB200/AT2221 at doses and routes as described in the legend for Figure 2. The white part of gastrocnemius was collected 14 days after the last administration. To assess the quality of muscle bundles, each sample was mounted in 90% glycerol in a chamber made with spacers between a slide and a coverslip. The fibers were then excited at 870 nm to collect the SHG imaging signal (green) and the 2-photon excited fluorescence signal (2PEF, red) as previously described (53). SHG reflects the position and organization of myosin heavy chain, while 2PEF reflects mitochondria and autofluorescent particles such as lipofuscin. WT fibers show a well-organized SHG signal and little 2PEF except where mitochondria are concentrated along the blood vessels at the surface of one of the fibers (arrowhead). In contrast, fibers from vehicle-treated and alglucosidase alfa–treated Gaa-KO mice show long interruptions of the SHG image that are rich in 2PEF-positive particles (arrows); these areas correspond to the space occupied by autophagic debris. In ATB200/AT2221–treated mice, some areas still show such a defect (arrows), but many areas appear indistinguishable from WT. Scale bars: 25 μm.