Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates

Helena Costa-Verdera, Fanny Collaud, Christopher R. Riling, Pauline Sellier, Jayme M. L. Nordin, G. Michael Preston, Umut Cagin, Julien Fabregue, Simon Barral, Maryse Moya-Nilges, Jacomina Krijnse-Locker, Laetitia Wittenberghe, Natalie Daniele, Bernard Gjata, Jeremie Cosette, Catalina Abad, Marcelo Simon-Sola, Severine Charles, Mathew Li, Marco Crosariol, Tom Antrilli, William J. Quinn, David A. Gross, Olivier Boyer, Xavier M. Anguela, Sean M. Armour, Pasqualina Colella, Giuseppe Ronzitti and Federico Mingozzi ()
Additional contact information
Helena Costa-Verdera: Genethon
Fanny Collaud: Genethon
Christopher R. Riling: Spark Therapeutics
Pauline Sellier: Genethon
Jayme M. L. Nordin: Spark Therapeutics
G. Michael Preston: Spark Therapeutics
Umut Cagin: Genethon
Julien Fabregue: Genethon
Simon Barral: Genethon
Maryse Moya-Nilges: Pasteur Institute
Jacomina Krijnse-Locker: Pasteur Institute
Laetitia Wittenberghe: Genethon
Natalie Daniele: Genethon
Bernard Gjata: Genethon
Jeremie Cosette: Genethon
Catalina Abad: Université de Rouen Normandie-IRIB
Marcelo Simon-Sola: Genethon
Severine Charles: Genethon
Mathew Li: Spark Therapeutics
Marco Crosariol: Spark Therapeutics
Tom Antrilli: Spark Therapeutics
William J. Quinn: Spark Therapeutics
David A. Gross: Genethon
Olivier Boyer: Université de Rouen Normandie-IRIB
Xavier M. Anguela: Spark Therapeutics
Sean M. Armour: Spark Therapeutics
Pasqualina Colella: Genethon
Giuseppe Ronzitti: Genethon
Federico Mingozzi: Genethon

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Pompe 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.

Date: 2021
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DOI: 10.1038/s41467-021-26744-4

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