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

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.

SUBMITTER: Costa-Verdera H

PROVIDER: S-EPMC8568898 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Costa-Verdera Helena H Collaud Fanny F Riling Christopher R CR Sellier Pauline P Nordin Jayme M L JML Preston G Michael GM Cagin Umut U Fabregue Julien J Barral Simon S Moya-Nilges Maryse M Krijnse-Locker Jacomina J van Wittenberghe Laetitia L Daniele Natalie N Gjata Bernard B Cosette Jeremie J Abad Catalina C Simon-Sola Marcelo M Charles Severine S Li Mathew M Crosariol Marco M Antrilli Tom T Quinn William J WJ Gross David A DA Boyer Olivier O Anguela Xavier M XM Armour Sean M SM Colella Pasqualina P Ronzitti Giuseppe G Mingozzi Federico F

Nature communications 20211104 1

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 ...[more]

PMID: 34737297

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Project description:BackgroundGiven the central importance of anti-malarial drugs in the treatment of malaria, there is a need to understand the effect of Plasmodium infection on the broad spectrum of drug metabolizing enzymes. Previous studies have shown reduced clearance of quinine, a treatment for Plasmodium infection, in individuals with malaria.MethodsThe hepatic expression of a large panel of drug metabolizing enzymes was studied in the livers of mice infected with the AS strain of Plasmodium chabaudi chabaudi, a nonlethal parasite in most strains of mice with several features that model human Plasmodium infections. C57BL/6J mice were infected with P. chabaudi by intraperitoneal injection of infected erythrocytes and sacrificed at different times after infection. Relative hepatic mRNA levels of various drug metabolizing enzymes, cytokines and acute phase proteins were measured by reverse transcriptase-real time PCR. Relative levels of cytochrome P450 proteins were measured by Western blotting with IR-dye labelled antibodies. Pharmacokinetics of 5 prototypic cytochrome P450 substrate drugs were measured by cassette dosing and high-resolution liquid chromatography-mass spectrometry. The results were analysed by MANOVA and post hoc univariate analysis of variance.ResultsThe great majority of enzyme mRNAs were down-regulated, with the greatest effects occurring at the peak of parasitaemia 8 days post infection. Protein levels of cytochrome P450 enzymes in the Cyp 2b, 2c, 2d, 2e, 3a and 4a subfamilies were also down-regulated. Several distinct groups differing in their temporal patterns of regulation were identified. The cassette dosing study revealed that at the peak of parasitaemia, the clearances of caffeine, bupropion, tolbutamide and midazolam were markedly reduced by 60-70%.ConclusionsThese findings in a model of uncomplicated human malaria suggest that changes in drug clearance in this condition may be of sufficient magnitude to cause significant alterations in exposure and response of anti-malarial drugs and co-medications.

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

Publications

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

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