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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 1

ATB200 is stabilized by the small-molecule pharmacological chaperone, AT2221.

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ATB200 is stabilized by the small-molecule pharmacological chaperone, AT...
(A) AT2221 (N-butyl-deoxynojirimycin, miglustat) binds to and stabilizes ATB200 due to its structural similarity to the terminal glucose residue of glycogen, the natural substrate for acid α-glucosidase (GAA). (B) Thermostability of ATB200 alone at neutral (7.4) or acidic (5.2) pH, or in the presence of increasing concentrations of AT2221 at pH 7.4. Unfolding of ATB200 was monitored by the increase in the fluorescence of SYPRO Orange as a function of temperature. (C and D) Time course for ATB200 inactivation (i.e., loss of activity) at 37°C in PBS, pH 7.4 (C) or in human blood ex vivo (D) with and without AT2221. GAA activity at various time points was normalized to the corresponding value at time 0 (baseline activities of ATB200 alone and with 17 μM or 170 μM AT2221 were 28, 18, and 17 μmol 4MU/ml/h, respectively). (E) Pharmacokinetic (PK) profile of ATB200 (100 mg/kg) alone or with oral coadministration of AT2221 (175 mg/kg; 30 minutes prior to a 2‑hour continuous i.v. infusion of ATB200) in cynomolgus monkeys. Blood samples were collected at the indicated time points and the PK was determined based on plasma GAA activity. n = 4 males and 4 females per group. Data represent mean ± SD. **P < 0.01, ***P < 0.001 by unpaired 2-sided t test between ATB200 with and without AT2221 at each time point.

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