Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model
Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here w...
| Autores: | , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/114668 |
| Acceso en línea: | https://hdl.handle.net/10171/114668 |
| Access Level: | acceso abierto |
| Palabra clave: | Anc80 Adeno-associated virus (AAV) vector Gene therapy Inborn error of metabolism Phenylketonuria |
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Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse modelKaiser, R.A. (Robert A.)|||/items/6afaab0e-3d47-4541-a40f-947f73ea3b45Weber, N.D. (Nicholas D.)|||/items/e84412f9-7e7c-4020-b16d-668a3fb5ee6aTrigueros-Motos, L. (Laia)|||/items/89a0169c-ea93-47f8-8ddc-3cc131ddf8ffAllen, K.L. (Kari L.)|||/items/c26aec3c-708d-4b93-8b93-bbd4bb96efb6Martinez, M. (Michael)|||/items/dd67ec2e-30a3-4713-9ded-add0d05bc93fCao, W. (William)|||/items/7fbfad2f-27f3-41ce-8305-ac2ec305b263VanLith, C.J. ( Caitlin J.)|||/items/3dac9023-ec85-431e-8501-97e2a68abb5fHillin, L.G. (Lori G.)|||/items/aa6fe4bd-dfd9-46fe-90cf-e4636dabe3aeDouar, A. (Anne)|||/items/a33dbbfb-3e78-4cfa-8f99-0652529ecd64González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191acAldabe, R. (Rafael)|||/items/ef60614f-7fda-4565-bd52-0ace35b55292Lillegard, J.B. (Joseph B.)|||/items/d2ed228b-2b19-4910-a1bf-7f690782040aAnc80Adeno-associated virus (AAV) vectorGene therapyInborn error of metabolismPhenylketonuriaPhenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.Wiley Periodicals LLC.Dadun. Depósito Académico Digital Universidad de Navarra20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/114668reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1146682026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| title |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| spellingShingle |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model Kaiser, R.A. (Robert A.)|||/items/6afaab0e-3d47-4541-a40f-947f73ea3b45 Anc80 Adeno-associated virus (AAV) vector Gene therapy Inborn error of metabolism Phenylketonuria |
| title_short |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| title_full |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| title_fullStr |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| title_full_unstemmed |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| title_sort |
Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model |
| dc.creator.none.fl_str_mv |
Kaiser, R.A. (Robert A.)|||/items/6afaab0e-3d47-4541-a40f-947f73ea3b45 Weber, N.D. (Nicholas D.)|||/items/e84412f9-7e7c-4020-b16d-668a3fb5ee6a Trigueros-Motos, L. (Laia)|||/items/89a0169c-ea93-47f8-8ddc-3cc131ddf8ff Allen, K.L. (Kari L.)|||/items/c26aec3c-708d-4b93-8b93-bbd4bb96efb6 Martinez, M. (Michael)|||/items/dd67ec2e-30a3-4713-9ded-add0d05bc93f Cao, W. (William)|||/items/7fbfad2f-27f3-41ce-8305-ac2ec305b263 VanLith, C.J. ( Caitlin J.)|||/items/3dac9023-ec85-431e-8501-97e2a68abb5f Hillin, L.G. (Lori G.)|||/items/aa6fe4bd-dfd9-46fe-90cf-e4636dabe3ae Douar, A. (Anne)|||/items/a33dbbfb-3e78-4cfa-8f99-0652529ecd64 González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac Aldabe, R. (Rafael)|||/items/ef60614f-7fda-4565-bd52-0ace35b55292 Lillegard, J.B. (Joseph B.)|||/items/d2ed228b-2b19-4910-a1bf-7f690782040a |
| author |
Kaiser, R.A. (Robert A.)|||/items/6afaab0e-3d47-4541-a40f-947f73ea3b45 |
| author_facet |
Kaiser, R.A. (Robert A.)|||/items/6afaab0e-3d47-4541-a40f-947f73ea3b45 Weber, N.D. (Nicholas D.)|||/items/e84412f9-7e7c-4020-b16d-668a3fb5ee6a Trigueros-Motos, L. (Laia)|||/items/89a0169c-ea93-47f8-8ddc-3cc131ddf8ff Allen, K.L. (Kari L.)|||/items/c26aec3c-708d-4b93-8b93-bbd4bb96efb6 Martinez, M. (Michael)|||/items/dd67ec2e-30a3-4713-9ded-add0d05bc93f Cao, W. (William)|||/items/7fbfad2f-27f3-41ce-8305-ac2ec305b263 VanLith, C.J. ( Caitlin J.)|||/items/3dac9023-ec85-431e-8501-97e2a68abb5f Hillin, L.G. (Lori G.)|||/items/aa6fe4bd-dfd9-46fe-90cf-e4636dabe3ae Douar, A. (Anne)|||/items/a33dbbfb-3e78-4cfa-8f99-0652529ecd64 González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac Aldabe, R. (Rafael)|||/items/ef60614f-7fda-4565-bd52-0ace35b55292 Lillegard, J.B. (Joseph B.)|||/items/d2ed228b-2b19-4910-a1bf-7f690782040a |
| author_role |
author |
| author2 |
Weber, N.D. (Nicholas D.)|||/items/e84412f9-7e7c-4020-b16d-668a3fb5ee6a Trigueros-Motos, L. (Laia)|||/items/89a0169c-ea93-47f8-8ddc-3cc131ddf8ff Allen, K.L. (Kari L.)|||/items/c26aec3c-708d-4b93-8b93-bbd4bb96efb6 Martinez, M. (Michael)|||/items/dd67ec2e-30a3-4713-9ded-add0d05bc93f Cao, W. (William)|||/items/7fbfad2f-27f3-41ce-8305-ac2ec305b263 VanLith, C.J. ( Caitlin J.)|||/items/3dac9023-ec85-431e-8501-97e2a68abb5f Hillin, L.G. (Lori G.)|||/items/aa6fe4bd-dfd9-46fe-90cf-e4636dabe3ae Douar, A. (Anne)|||/items/a33dbbfb-3e78-4cfa-8f99-0652529ecd64 González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac Aldabe, R. (Rafael)|||/items/ef60614f-7fda-4565-bd52-0ace35b55292 Lillegard, J.B. (Joseph B.)|||/items/d2ed228b-2b19-4910-a1bf-7f690782040a |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Anc80 Adeno-associated virus (AAV) vector Gene therapy Inborn error of metabolism Phenylketonuria |
| topic |
Anc80 Adeno-associated virus (AAV) vector Gene therapy Inborn error of metabolism Phenylketonuria |
| description |
Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-01-01 2021 2021-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/114668 |
| url |
https://hdl.handle.net/10171/114668 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Wiley Periodicals LLC. |
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Wiley Periodicals LLC. |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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1869404608949911552 |
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15,812455 |