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Liver‐directed gene therapy for ornithine aminotransferase deficiency
Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop p...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086579/ https://www.ncbi.nlm.nih.gov/pubmed/36647689 http://dx.doi.org/10.15252/emmm.202217033 |
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author | Boffa, Iolanda Polishchuk, Elena De Stefano, Lucia Dell'Aquila, Fabio Nusco, Edoardo Marrocco, Elena Audano, Matteo Pedretti, Silvia Caterino, Marianna Bellezza, Ilaria Ruoppolo, Margherita Mitro, Nico Cellini, Barbara Auricchio, Alberto Brunetti‐Pierri, Nicola |
author_facet | Boffa, Iolanda Polishchuk, Elena De Stefano, Lucia Dell'Aquila, Fabio Nusco, Edoardo Marrocco, Elena Audano, Matteo Pedretti, Silvia Caterino, Marianna Bellezza, Ilaria Ruoppolo, Margherita Mitro, Nico Cellini, Barbara Auricchio, Alberto Brunetti‐Pierri, Nicola |
author_sort | Boffa, Iolanda |
collection | PubMed |
description | Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno‐associated (AAV8) vector expressing OAT under the control of a hepatocyte‐specific promoter. Following injections, OAT‐deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV‐injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one‐year post‐injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof‐of‐concept of efficacy of liver‐directed AAV‐mediated gene therapy of GACR. |
format | Online Article Text |
id | pubmed-10086579 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100865792023-04-12 Liver‐directed gene therapy for ornithine aminotransferase deficiency Boffa, Iolanda Polishchuk, Elena De Stefano, Lucia Dell'Aquila, Fabio Nusco, Edoardo Marrocco, Elena Audano, Matteo Pedretti, Silvia Caterino, Marianna Bellezza, Ilaria Ruoppolo, Margherita Mitro, Nico Cellini, Barbara Auricchio, Alberto Brunetti‐Pierri, Nicola EMBO Mol Med Reports Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno‐associated (AAV8) vector expressing OAT under the control of a hepatocyte‐specific promoter. Following injections, OAT‐deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV‐injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one‐year post‐injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof‐of‐concept of efficacy of liver‐directed AAV‐mediated gene therapy of GACR. John Wiley and Sons Inc. 2023-01-17 /pmc/articles/PMC10086579/ /pubmed/36647689 http://dx.doi.org/10.15252/emmm.202217033 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Reports Boffa, Iolanda Polishchuk, Elena De Stefano, Lucia Dell'Aquila, Fabio Nusco, Edoardo Marrocco, Elena Audano, Matteo Pedretti, Silvia Caterino, Marianna Bellezza, Ilaria Ruoppolo, Margherita Mitro, Nico Cellini, Barbara Auricchio, Alberto Brunetti‐Pierri, Nicola Liver‐directed gene therapy for ornithine aminotransferase deficiency |
title | Liver‐directed gene therapy for ornithine aminotransferase deficiency |
title_full | Liver‐directed gene therapy for ornithine aminotransferase deficiency |
title_fullStr | Liver‐directed gene therapy for ornithine aminotransferase deficiency |
title_full_unstemmed | Liver‐directed gene therapy for ornithine aminotransferase deficiency |
title_short | Liver‐directed gene therapy for ornithine aminotransferase deficiency |
title_sort | liver‐directed gene therapy for ornithine aminotransferase deficiency |
topic | Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086579/ https://www.ncbi.nlm.nih.gov/pubmed/36647689 http://dx.doi.org/10.15252/emmm.202217033 |
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