Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates
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Published:2021-11-04
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Costa-Verdera HelenaORCID, Collaud FannyORCID, Riling Christopher R., Sellier Pauline, Nordin Jayme M. L., Preston G. Michael, Cagin Umut, Fabregue Julien, Barral Simon, Moya-Nilges Maryse, Krijnse-Locker Jacomina, van Wittenberghe Laetitia, Daniele Natalie, Gjata Bernard, Cosette Jeremie, Abad Catalina, Simon-Sola Marcelo, Charles Severine, Li Mathew, Crosariol Marco, Antrilli Tom, Quinn William J., Gross David A., Boyer OlivierORCID, Anguela Xavier M., Armour Sean M.ORCID, Colella PasqualinaORCID, Ronzitti GiuseppeORCID, Mingozzi FedericoORCID
Abstract
AbstractPompe disease (PD) is a severe neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). PD is currently treated with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human GAA (rhGAA). Although the introduction of ERT represents a breakthrough in the management of PD, the approach suffers from several shortcomings. Here, we developed a mouse model of PD to compare the efficacy of hepatic gene transfer with adeno-associated virus (AAV) vectors expressing secretable GAA with long-term ERT. Liver expression of GAA results in enhanced pharmacokinetics and uptake of the enzyme in peripheral tissues compared to ERT. Combination of gene transfer with pharmacological chaperones boosts GAA bioavailability, resulting in improved rescue of the PD phenotype. Scale-up of hepatic gene transfer to non-human primates also successfully results in enzyme secretion in blood and uptake in key target tissues, supporting the ongoing clinical translation of the approach.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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