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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 8

Long-term administration of ATB200/AT2221 improves muscle function in Gaa-KO mice.

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Long-term administration of ATB200/AT2221 improves muscle function in Ga...
Fourteen-week-old male Gaa-KO mice received 10 biweekly administrations of vehicle, alglucosidase alfa, or ATB200/AT2221 at doses and routes as described in the legend for Figure 2. A group of age-matched untreated WT mice was included for comparison. Muscle strength was assessed using grip-strength (A) and wire-hang (B) tests every month. Data represent the mean ± SEM. n = 12–15 mice/group for baseline and the first 3 months; n = 6–8 mice/group for months 4 and 5 (7 animals from each group were euthanized after 3 months for interim analysis). Multiple comparison was performed for grip-strength and wire-hang data using 1-way ANOVA and nonparametric statistical analysis, respectively. #P < 0.05, ##P < 0.01, ####P < 0.0001 compared with WT group. ^^P < 0.01, ^^^P < 0.001, ^^^^P < 0.0001 compared with vehicle group. **P < 0.01, ***P < 0.001 compared with alglucosidase alfa group. After 2 additional administrations (12 total), tissues were collected 14 days after the last administration for histologic assessment (C–E). (C) Histogram showing the relative fiber size distribution frequency in quadriceps based on a bin size of 10 μm in Min FD. The Min FD values within each bin were greater than the lower limit and did not exceed the upper limit. The average distribution frequency for fibers with Min FD not exceeding 5 μm or larger than 85 μm was less than 0.1% and thus not included in the graph. Number of fibers analyzed per mouse is indicated in Supplemental Table 1. Error bars are SD. (D) Min FD across different groups. Individual values and mean ± SD are shown (n = 5–6 per group). ns, not significant. *P < 0.05; **P < 0.01; ****P < 0.0001 by Tukey’s multiple comparison under 1-way ANOVA. For C and D, more than 20,000 fibers were analyzed for each of the treated groups and more than 16,000 fibers for the WT (see also Supplemental Table 1). (E) Representative images of dysferlin-stained sections of muscle samples from quadriceps and triceps. n = 6–7 per group. Note that the extensive vacuolar change in all samples was the result of freezing artifact. Original magnification, ×200. Scale bars: 100 μm.
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