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Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses

BACKGROUND: Achieving persistent expression is a prerequisite for genetic therapies for inherited metabolic enzymopathies. Such disorders potentially could be treated with gene therapy shortly after birth to prevent pathology. However, rapid cell turnover leads to hepatic episomal vector loss, which...

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Autores principales: Tai, Denise S., Hu, Chuhong, Kim, Elizabeth H., Lipshutz, Gerald S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540625/
https://www.ncbi.nlm.nih.gov/pubmed/26042522
http://dx.doi.org/10.1038/pr.2015.109
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author Tai, Denise S.
Hu, Chuhong
Kim, Elizabeth H.
Lipshutz, Gerald S.
author_facet Tai, Denise S.
Hu, Chuhong
Kim, Elizabeth H.
Lipshutz, Gerald S.
author_sort Tai, Denise S.
collection PubMed
description BACKGROUND: Achieving persistent expression is a prerequisite for genetic therapies for inherited metabolic enzymopathies. Such disorders potentially could be treated with gene therapy shortly after birth to prevent pathology. However, rapid cell turnover leads to hepatic episomal vector loss, which diminishes effectiveness. The current studies assessed whether tolerance to transgene proteins expressed in the neonatal period is durable and if the expression may be augmented with subsequent adeno-associated virus (AAV) administration. METHODS: AAV was administered to mice on day two with re-injection at 14 or at 14 and 42 days with examination of changes in hepatic copies and B and T cell-mediated immune responses. RESULTS: Immune responses to the transgene protein and AAV were absent after neonatal administration. Re-injection at 14 or at 14 and 42 days resulted in augmented expression with greater hepatic genome copies. Unlike controls, immune responses to transgene proteins were not detected in animals injected as neonates and subsequently. However, while no immune response developed after neonatal administration, anticapsid immune responses developed with further injections suggesting immunological ignorance was the initial mechanism of unresponsiveness. CONCLUSIONS: Persistence of transgene protein allows for tolerance induction permitting readministration of AAV to re-establish protein levels that decline with growth.
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spelling pubmed-45406252016-03-01 Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses Tai, Denise S. Hu, Chuhong Kim, Elizabeth H. Lipshutz, Gerald S. Pediatr Res Article BACKGROUND: Achieving persistent expression is a prerequisite for genetic therapies for inherited metabolic enzymopathies. Such disorders potentially could be treated with gene therapy shortly after birth to prevent pathology. However, rapid cell turnover leads to hepatic episomal vector loss, which diminishes effectiveness. The current studies assessed whether tolerance to transgene proteins expressed in the neonatal period is durable and if the expression may be augmented with subsequent adeno-associated virus (AAV) administration. METHODS: AAV was administered to mice on day two with re-injection at 14 or at 14 and 42 days with examination of changes in hepatic copies and B and T cell-mediated immune responses. RESULTS: Immune responses to the transgene protein and AAV were absent after neonatal administration. Re-injection at 14 or at 14 and 42 days resulted in augmented expression with greater hepatic genome copies. Unlike controls, immune responses to transgene proteins were not detected in animals injected as neonates and subsequently. However, while no immune response developed after neonatal administration, anticapsid immune responses developed with further injections suggesting immunological ignorance was the initial mechanism of unresponsiveness. CONCLUSIONS: Persistence of transgene protein allows for tolerance induction permitting readministration of AAV to re-establish protein levels that decline with growth. 2015-06-04 2015-09 /pmc/articles/PMC4540625/ /pubmed/26042522 http://dx.doi.org/10.1038/pr.2015.109 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Tai, Denise S.
Hu, Chuhong
Kim, Elizabeth H.
Lipshutz, Gerald S.
Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses
title Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses
title_full Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses
title_fullStr Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses
title_full_unstemmed Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses
title_short Augmentation of Transgene-Encoded Protein After Neonatal Injection of Adeno-Associated Virus Improves Hepatic Copy Number Without Immune Responses
title_sort augmentation of transgene-encoded protein after neonatal injection of adeno-associated virus improves hepatic copy number without immune responses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540625/
https://www.ncbi.nlm.nih.gov/pubmed/26042522
http://dx.doi.org/10.1038/pr.2015.109
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