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Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates
- Source :
- Nature Communications, Nature Communications, 2021, 12 (1), pp.6393. ⟨10.1038/s41467-021-26744-4⟩, Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021), Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.6393. ⟨10.1038/s41467-021-26744-4⟩
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
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.<br />Pompe disease is currently treated with enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (GAA). Here, the authors show hepatic-directed gene therapy with AAV vectors enhances GAA bioavailability compared with ERT, resulting in improved rescue of the disease phenotype in mice and broad enzyme distribution in mice and non-human primates.
- Subjects :
- Male
congenital, hereditary, and neonatal diseases and abnormalities
Genetic enhancement
Science
Metabolic disorders
General Physics and Astronomy
Pharmacology
General Biochemistry, Genetics and Molecular Biology
Virus
Article
law.invention
03 medical and health sciences
Mice
0302 clinical medicine
Gene therapy
Pharmacokinetics
law
Autophagy
Distribution (pharmacology)
Medicine
Animals
Enzyme Replacement Therapy
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Multidisciplinary
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
business.industry
Glycogen Storage Disease Type II
nutritional and metabolic diseases
alpha-Glucosidases
General Chemistry
Enzyme replacement therapy
Phenotype
3. Good health
Enzyme
chemistry
Liver
Recombinant DNA
Female
business
030217 neurology & neurosurgery
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications, Nature Communications, 2021, 12 (1), pp.6393. ⟨10.1038/s41467-021-26744-4⟩, Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021), Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.6393. ⟨10.1038/s41467-021-26744-4⟩
- Accession number :
- edsair.doi.dedup.....9a1664cfde76136fe6521768528975a1