1. Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates.
- Author
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Costa-Verdera H, Collaud F, Riling CR, Sellier P, Nordin JML, Preston GM, Cagin U, Fabregue J, Barral S, Moya-Nilges M, Krijnse-Locker J, van Wittenberghe L, Daniele N, Gjata B, Cosette J, Abad C, Simon-Sola M, Charles S, Li M, Crosariol M, Antrilli T, Quinn WJ 3rd, Gross DA, Boyer O, Anguela XM, Armour SM, Colella P, Ronzitti G, and Mingozzi F
- Subjects
- Animals, Autophagy, Enzyme Replacement Therapy, Female, Glycogen Storage Disease Type II therapy, Liver enzymology, Male, Mice, alpha-Glucosidases genetics, Glycogen Storage Disease Type II enzymology, alpha-Glucosidases metabolism
- 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., (© 2021. The Author(s).)
- Published
- 2021
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