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Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse
Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-N-acetylglucosaminidase. It is characterized by severe and complex central nervous system degeneration. Effective therapies will likely target early onset disease and...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149485/ https://www.ncbi.nlm.nih.gov/pubmed/33244179 http://dx.doi.org/10.1038/s41434-020-00206-w |
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author | Gilkes, Janine A. Judkins, Benjamin L. Herrera, Brontie N. Mandel, Ronald J. Boye, Sanford L. Boye, Shannon E. Srivastava, Arun Heldermon, Coy D. |
author_facet | Gilkes, Janine A. Judkins, Benjamin L. Herrera, Brontie N. Mandel, Ronald J. Boye, Sanford L. Boye, Shannon E. Srivastava, Arun Heldermon, Coy D. |
author_sort | Gilkes, Janine A. |
collection | PubMed |
description | Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-N-acetylglucosaminidase. It is characterized by severe and complex central nervous system degeneration. Effective therapies will likely target early onset disease and overcome the blood–brain barrier. Modifications of adeno-associated viral (AAV) vector capsids that enhance transduction efficiency have been described in the retina. Herein, we describe for the first time, a transduction assessment of two intracranially administered adeno-associated virus serotype 8 variants, in which specific surface-exposed tyrosine (Y) and threonine (T) residues were substituted with phenylalanine (F) and valine (V) residues, respectively. A double-mutant (Y447 + 733F) and a triple-mutant (Y447 + 733F + T494V) AAV8 were evaluated for their efficacy for the potential treatment of MPS IIIB in a neonatal setting. We evaluated biodistribution and transduction profiles of both variants compared to the unmodified parental AAV8, and assessed whether the method of vector administration would modulate their utility. Vectors were administered through four intracranial routes: six sites (IC6), thalamic (T), intracerebroventricular, and ventral tegmental area into neonatal mice. Overall, we conclude that the IC6 method resulted in the widest biodistribution within the brain. Noteworthy, we demonstrate that GFP intensity was significantly more robust with AAV8 (double Y–F + T–V) compared to AAV8 (double Y–F). This provides proof of concept for the enhanced utility of IC6 administration of the capsid modified AAV8 (double Y–F + T–V) as a valid therapeutic approach for the treatment of MPS IIIB, with further implications for other monogenic diseases. |
format | Online Article Text |
id | pubmed-8149485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81494852021-08-23 Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse Gilkes, Janine A. Judkins, Benjamin L. Herrera, Brontie N. Mandel, Ronald J. Boye, Sanford L. Boye, Shannon E. Srivastava, Arun Heldermon, Coy D. Gene Ther Article Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-N-acetylglucosaminidase. It is characterized by severe and complex central nervous system degeneration. Effective therapies will likely target early onset disease and overcome the blood–brain barrier. Modifications of adeno-associated viral (AAV) vector capsids that enhance transduction efficiency have been described in the retina. Herein, we describe for the first time, a transduction assessment of two intracranially administered adeno-associated virus serotype 8 variants, in which specific surface-exposed tyrosine (Y) and threonine (T) residues were substituted with phenylalanine (F) and valine (V) residues, respectively. A double-mutant (Y447 + 733F) and a triple-mutant (Y447 + 733F + T494V) AAV8 were evaluated for their efficacy for the potential treatment of MPS IIIB in a neonatal setting. We evaluated biodistribution and transduction profiles of both variants compared to the unmodified parental AAV8, and assessed whether the method of vector administration would modulate their utility. Vectors were administered through four intracranial routes: six sites (IC6), thalamic (T), intracerebroventricular, and ventral tegmental area into neonatal mice. Overall, we conclude that the IC6 method resulted in the widest biodistribution within the brain. Noteworthy, we demonstrate that GFP intensity was significantly more robust with AAV8 (double Y–F + T–V) compared to AAV8 (double Y–F). This provides proof of concept for the enhanced utility of IC6 administration of the capsid modified AAV8 (double Y–F + T–V) as a valid therapeutic approach for the treatment of MPS IIIB, with further implications for other monogenic diseases. Nature Publishing Group UK 2020-11-26 2021 /pmc/articles/PMC8149485/ /pubmed/33244179 http://dx.doi.org/10.1038/s41434-020-00206-w Text en © The Author(s), under exclusive licence to Springer Nature Limited 2020, corrected publication 2023 https://creativecommons.org/licenses/by-nc/4.0/Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Article Gilkes, Janine A. Judkins, Benjamin L. Herrera, Brontie N. Mandel, Ronald J. Boye, Sanford L. Boye, Shannon E. Srivastava, Arun Heldermon, Coy D. Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse |
title | Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse |
title_full | Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse |
title_fullStr | Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse |
title_full_unstemmed | Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse |
title_short | Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse |
title_sort | site-specific modifications to aav8 capsid yields enhanced brain transduction in the neonatal mps iiib mouse |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149485/ https://www.ncbi.nlm.nih.gov/pubmed/33244179 http://dx.doi.org/10.1038/s41434-020-00206-w |
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