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Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children

Recombinant AAV serotype vectors and their variants have been or are currently being used for gene therapy for hemophilia in several phase I/II/III clinical trials in humans. However, none of these trials have included children with hemophilia since the traditional liver-directed AAV gene therapy wi...

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Autores principales: Shoti, Jakob, Qing, Keyun, Srivastava, Arun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9583144/
https://www.ncbi.nlm.nih.gov/pubmed/36274690
http://dx.doi.org/10.3389/fmicb.2022.1033615
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author Shoti, Jakob
Qing, Keyun
Srivastava, Arun
author_facet Shoti, Jakob
Qing, Keyun
Srivastava, Arun
author_sort Shoti, Jakob
collection PubMed
description Recombinant AAV serotype vectors and their variants have been or are currently being used for gene therapy for hemophilia in several phase I/II/III clinical trials in humans. However, none of these trials have included children with hemophilia since the traditional liver-directed AAV gene therapy will not work in these patients because of the following reasons: (i) Up until age 10–12, the liver is still growing and dividing, and with every cell division, the AAV vector genomes will be diluted out due to their episomal nature; and (ii) Repeated gene delivery will be needed, but repeat dosing, even with an ideal AAV vector is not an option because of pre-existing antibodies to AAV vectors following the first administration. Here we describe the development of an optimized human Factor IX (hF.IX) gene expression cassette under the control of a human liver-specific transthyretin promoter covalently flanked by AAV inverted terminal repeats (ITRs) with no open ends (optNE-TTR-hF.IX), which mediated ~sixfold higher hF.IX levels than that from a linear TTR-hF.IX DNA construct in human hepatoma cells up to four-weeks post-transfection. In future studies, encapsidation of the optNE-TTR-hF.IX DNA in liver-targeted synthetic liposomes, may provide a viable approach for the potential gene therapy for hemophilia in children.
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spelling pubmed-95831442022-10-21 Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children Shoti, Jakob Qing, Keyun Srivastava, Arun Front Microbiol Microbiology Recombinant AAV serotype vectors and their variants have been or are currently being used for gene therapy for hemophilia in several phase I/II/III clinical trials in humans. However, none of these trials have included children with hemophilia since the traditional liver-directed AAV gene therapy will not work in these patients because of the following reasons: (i) Up until age 10–12, the liver is still growing and dividing, and with every cell division, the AAV vector genomes will be diluted out due to their episomal nature; and (ii) Repeated gene delivery will be needed, but repeat dosing, even with an ideal AAV vector is not an option because of pre-existing antibodies to AAV vectors following the first administration. Here we describe the development of an optimized human Factor IX (hF.IX) gene expression cassette under the control of a human liver-specific transthyretin promoter covalently flanked by AAV inverted terminal repeats (ITRs) with no open ends (optNE-TTR-hF.IX), which mediated ~sixfold higher hF.IX levels than that from a linear TTR-hF.IX DNA construct in human hepatoma cells up to four-weeks post-transfection. In future studies, encapsidation of the optNE-TTR-hF.IX DNA in liver-targeted synthetic liposomes, may provide a viable approach for the potential gene therapy for hemophilia in children. Frontiers Media S.A. 2022-10-06 /pmc/articles/PMC9583144/ /pubmed/36274690 http://dx.doi.org/10.3389/fmicb.2022.1033615 Text en Copyright © 2022 Shoti, Qing and Srivastava. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Shoti, Jakob
Qing, Keyun
Srivastava, Arun
Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children
title Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children
title_full Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children
title_fullStr Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children
title_full_unstemmed Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children
title_short Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children
title_sort development of an aav dna-based synthetic vector for the potential gene therapy of hemophilia in children
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9583144/
https://www.ncbi.nlm.nih.gov/pubmed/36274690
http://dx.doi.org/10.3389/fmicb.2022.1033615
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