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Improved efficacy of a next-generation ERT in murine Pompe disease
Su Xu, … , Nina Raben, Richie Khanna
Su Xu, … , Nina Raben, Richie Khanna
Published March 7, 2019
Citation Information: JCI Insight. 2019;4(5):e125358. https://doi.org/10.1172/jci.insight.125358.
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Research Article Genetics Therapeutics

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

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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 2

ATB200/AT2221 exhibits better glycogen clearance and greater lysosomal targeting in vivo compared with alglucosidase alfa.

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ATB200/AT2221 exhibits better glycogen clearance and greater lysosomal t...
Male Gaa-KO mice (14–16 weeks old) received 2 (A and B) or 6 (C) biweekly i.v. administrations of vehicle, 20 mg/kg alglucosidase alfa, or 20 mg/kg ATB200/AT2221 (10 mg/kg AT2221 was administered orally 30 minutes prior to ATB200 i.v. injection). Tissues were collected 14 days after the last administration. (A) Glycogen levels in different skeletal muscles and in the heart. Individual values and mean ± SD are shown. n = 6–8 animals per group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by Tukey’s multiple comparison under 1-way ANOVA. (B) PAS staining for glycogen in paraffin sections of muscle tissues. n = 6–8 animals per group. Original magnification, ×200. Scale bars: 100 μm. (C) PAS staining for glycogen in cardiac vascular smooth muscle cells (vSMCs). n = 7 animals per group. Original magnification, ×400. Scale bars: 50 μm. (D) Western blot of muscle lysates from quadriceps and diaphragm derived from 22-week-old alglucosidase alfa– and ATB200/AT2221–treated mice after a single administration. Tissues were collected 3 days after administration.
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