Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease
We developed a novel adeno-associated virus 5 gene therapy (AAV5-GLA) expressing human alpha-galactosidase A (GLA) under the control of a novel, small and strong, liver-restricted promoter. We assessed the preclinical potential of AAV5-GLA for treating Fabry disease, an X-linked hereditary metabolic...
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Elsevier
2024-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124001918 |
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| author | Jolanda M.P. Liefhebber Giso Brasser Elisabeth A. Spronck Roelof Ottenhoff Lieke Paerels Maria J. Ferraz Lukas K. Schwarz Nikoleta Efthymiopoulou Chi-Lin Kuo Paula S. Montenegro-Miranda Melvin M. Evers Johannes M.F.G. Aerts Ying Poi Liu |
| author_facet | Jolanda M.P. Liefhebber Giso Brasser Elisabeth A. Spronck Roelof Ottenhoff Lieke Paerels Maria J. Ferraz Lukas K. Schwarz Nikoleta Efthymiopoulou Chi-Lin Kuo Paula S. Montenegro-Miranda Melvin M. Evers Johannes M.F.G. Aerts Ying Poi Liu |
| author_sort | Jolanda M.P. Liefhebber |
| collection | DOAJ |
| description | We developed a novel adeno-associated virus 5 gene therapy (AAV5-GLA) expressing human alpha-galactosidase A (GLA) under the control of a novel, small and strong, liver-restricted promoter. We assessed the preclinical potential of AAV5-GLA for treating Fabry disease, an X-linked hereditary metabolic disorder resulting from mutations in the gene encoding GLA that lead to accumulation of the substrates globotriaosylceramide and globotriaosylsphingosine, causing heart, kidney, and central nervous system dysfunction. Effects of intravenously administered AAV5-GLA were evaluated in (1) GLA-knockout mice aged 7–8 weeks (early in disease) and 20 weeks (nociception phenotype manifestation) and (2) cynomolgus macaques during an 8-week period. In both species, AAV5-GLA was observed as safe, generated detectable vector DNA and mRNA levels in liver, and produced stable enzyme activity in liver and plasma. In mice, dose-dependent transgene enzyme activity, cross-correction (substrate reduction) in kidney and heart, and improved nociception lasted over 6 months. Moreover, after delayed administration when animals displayed the nociception phenotype, target organ enzyme activity was present, and accumulated substrates were reduced. Given the strong, durable expression of active GLA with this promoter and favorable profile of adeno-associated virus 5-based gene therapy in humans, AAV5-GLA warrants further investigation in clinical trials for Fabry disease. |
| format | Article |
| id | doaj-art-aad76f27840e498791a89dfc62877743 |
| institution | OA Journals |
| issn | 2329-0501 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-aad76f27840e498791a89dfc628777432025-08-20T02:07:30ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012024-12-0132410137510.1016/j.omtm.2024.101375Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry diseaseJolanda M.P. Liefhebber0Giso Brasser1Elisabeth A. Spronck2Roelof Ottenhoff3Lieke Paerels4Maria J. Ferraz5Lukas K. Schwarz6Nikoleta Efthymiopoulou7Chi-Lin Kuo8Paula S. Montenegro-Miranda9Melvin M. Evers10Johannes M.F.G. Aerts11Ying Poi Liu12uniQure biopharma B.V., Amsterdam 1105 BP, the Netherlands; Corresponding author: Jolanda M.P. Liefhebber, Global Research, uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands.uniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsuniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsAmsterdam UMC, Amsterdam 1105 AZ, the NetherlandsuniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsLeiden Institute of Chemistry, Leiden University, Leiden 2333 CC, the NetherlandsuniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsuniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsLeiden Institute of Chemistry, Leiden University, Leiden 2333 CC, the Netherlands; VIB, 9052 Ghent, BelgiumuniQure biopharma B.V., Amsterdam 1105 BP, the Netherlands; VectorY Therapeutics B.V., Amsterdam 1098 XH, the NetherlandsuniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsLeiden Institute of Chemistry, Leiden University, Leiden 2333 CC, the NetherlandsuniQure biopharma B.V., Amsterdam 1105 BP, the NetherlandsWe developed a novel adeno-associated virus 5 gene therapy (AAV5-GLA) expressing human alpha-galactosidase A (GLA) under the control of a novel, small and strong, liver-restricted promoter. We assessed the preclinical potential of AAV5-GLA for treating Fabry disease, an X-linked hereditary metabolic disorder resulting from mutations in the gene encoding GLA that lead to accumulation of the substrates globotriaosylceramide and globotriaosylsphingosine, causing heart, kidney, and central nervous system dysfunction. Effects of intravenously administered AAV5-GLA were evaluated in (1) GLA-knockout mice aged 7–8 weeks (early in disease) and 20 weeks (nociception phenotype manifestation) and (2) cynomolgus macaques during an 8-week period. In both species, AAV5-GLA was observed as safe, generated detectable vector DNA and mRNA levels in liver, and produced stable enzyme activity in liver and plasma. In mice, dose-dependent transgene enzyme activity, cross-correction (substrate reduction) in kidney and heart, and improved nociception lasted over 6 months. Moreover, after delayed administration when animals displayed the nociception phenotype, target organ enzyme activity was present, and accumulated substrates were reduced. Given the strong, durable expression of active GLA with this promoter and favorable profile of adeno-associated virus 5-based gene therapy in humans, AAV5-GLA warrants further investigation in clinical trials for Fabry disease.http://www.sciencedirect.com/science/article/pii/S2329050124001918glycosphingolipidslysosomal storage diseasesMacaca fascicularismetabolismmiceknockout |
| spellingShingle | Jolanda M.P. Liefhebber Giso Brasser Elisabeth A. Spronck Roelof Ottenhoff Lieke Paerels Maria J. Ferraz Lukas K. Schwarz Nikoleta Efthymiopoulou Chi-Lin Kuo Paula S. Montenegro-Miranda Melvin M. Evers Johannes M.F.G. Aerts Ying Poi Liu Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease Molecular Therapy: Methods & Clinical Development glycosphingolipids lysosomal storage diseases Macaca fascicularis metabolism mice knockout |
| title | Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease |
| title_full | Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease |
| title_fullStr | Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease |
| title_full_unstemmed | Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease |
| title_short | Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease |
| title_sort | preclinical efficacy and safety of adeno associated virus 5 alpha galactosidase a gene therapy for fabry disease |
| topic | glycosphingolipids lysosomal storage diseases Macaca fascicularis metabolism mice knockout |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124001918 |
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