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Open AccessArticle

Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease

1
Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
2
Greenovation Biotech GmbH, 79108 Freiburg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(7), 2642; https://doi.org/10.3390/ijms21072642
Received: 9 March 2020 / Revised: 7 April 2020 / Accepted: 8 April 2020 / Published: 10 April 2020
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and the nervous system. Replacement therapy with the currently approved enzyme relies on M6P-mediated endocytosis. However, therapeutic outcomes still leave room for improvement, especially with regard to skeletal muscles. We tested the uptake, activity, and effect on glucose metabolism of a non-phosphorylated recombinant human GAA produced in moss (moss-GAA). Three variants of moss-GAA differing in glycosylation pattern have been analyzed: two with terminal mannose residues in a paucimannosidic (Man3) or high-mannose (Man 5) configuration and one with terminal N-acetylglucosamine residues (GnGn). Compared to alglucosidase alfa the moss-GAA GnGn variant showed increased uptake in differentiated myotubes. Moreover, incubation of immortalized muscle cells of Gaa−/− mice with moss-GAA GnGn led to similarly efficient clearance of accumulated glycogen as with alglucosidase alfa. These initial data suggest that M6P-residues might not always be necessary for the cellular uptake in enzyme replacement therapy (ERT) and indicate the potential of moss-GAA GnGn as novel alternative drug for targeting skeletal muscle in Pompe patients. View Full-Text
Keywords: Pompe disease; enzyme replacement therapy; glycogen storage disease type II; moss-GAA Pompe disease; enzyme replacement therapy; glycogen storage disease type II; moss-GAA
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Hintze, S.; Limmer, S.; Dabrowska-Schlepp, P.; Berg, B.; Krieghoff, N.; Busch, A.; Schaaf, A.; Meinke, P.; Schoser, B. Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease. Int. J. Mol. Sci. 2020, 21, 2642.

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