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Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery
A serious limitation of current adeno-associated viral (AAV) capsids employed for subretinal delivery is achieving adequate lateral spread beyond the injection site, required for the efficient delivery of gene therapy to the outer retina and/or RPE. AAVBR1 is a unique AAV with exceptional tropism fo...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317317/ https://www.ncbi.nlm.nih.gov/pubmed/35887086 http://dx.doi.org/10.3390/ijms23147738 |
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author | Carroll, Lara Uehara, Hironori Zhang, Xiaohui Ambati, Balamurali |
author_facet | Carroll, Lara Uehara, Hironori Zhang, Xiaohui Ambati, Balamurali |
author_sort | Carroll, Lara |
collection | PubMed |
description | A serious limitation of current adeno-associated viral (AAV) capsids employed for subretinal delivery is achieving adequate lateral spread beyond the injection site, required for the efficient delivery of gene therapy to the outer retina and/or RPE. AAVBR1 is a unique AAV with exceptional tropism for CNS microvasculature following systemic delivery. Here, we used in vivo and ex vivo analysis to show that subretinal delivery of AAVBR1.GFP in mice achieves superior tropism to RPE and outer retina than either AAV2.GFP or AAV8.GFP, two of the most common capsids used for subretinal delivery. At a low (5 × 10(8) vg) subretinal dose, the AAVBR1.GFP signal was visible by 48 h and significantly surpassed peak fluorescence of other AAVs in retina and RPE. The co-injection of AAVBR1.GFP with the AAVBR1-specific heptapeptide, NRGTEWD, significantly blocked the AAVBR1.GFP signal, but had no effect on AAV2.GFP fluorescence, confirming that AAVBR1’s enhanced tropism for RPE and outer retina derives from this 7AA modification within the capsid-binding motif. Enhanced dispersal and consequent transduction suggest that AAVBR1 can be employed at a lower dosage than the standard AAV2 capsid to achieve equivalent expression for gene therapy, warranting further evaluation of its utility as a therapeutic vehicle for subretinal delivery. |
format | Online Article Text |
id | pubmed-9317317 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93173172022-07-27 Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery Carroll, Lara Uehara, Hironori Zhang, Xiaohui Ambati, Balamurali Int J Mol Sci Communication A serious limitation of current adeno-associated viral (AAV) capsids employed for subretinal delivery is achieving adequate lateral spread beyond the injection site, required for the efficient delivery of gene therapy to the outer retina and/or RPE. AAVBR1 is a unique AAV with exceptional tropism for CNS microvasculature following systemic delivery. Here, we used in vivo and ex vivo analysis to show that subretinal delivery of AAVBR1.GFP in mice achieves superior tropism to RPE and outer retina than either AAV2.GFP or AAV8.GFP, two of the most common capsids used for subretinal delivery. At a low (5 × 10(8) vg) subretinal dose, the AAVBR1.GFP signal was visible by 48 h and significantly surpassed peak fluorescence of other AAVs in retina and RPE. The co-injection of AAVBR1.GFP with the AAVBR1-specific heptapeptide, NRGTEWD, significantly blocked the AAVBR1.GFP signal, but had no effect on AAV2.GFP fluorescence, confirming that AAVBR1’s enhanced tropism for RPE and outer retina derives from this 7AA modification within the capsid-binding motif. Enhanced dispersal and consequent transduction suggest that AAVBR1 can be employed at a lower dosage than the standard AAV2 capsid to achieve equivalent expression for gene therapy, warranting further evaluation of its utility as a therapeutic vehicle for subretinal delivery. MDPI 2022-07-13 /pmc/articles/PMC9317317/ /pubmed/35887086 http://dx.doi.org/10.3390/ijms23147738 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Carroll, Lara Uehara, Hironori Zhang, Xiaohui Ambati, Balamurali Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery |
title | Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery |
title_full | Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery |
title_fullStr | Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery |
title_full_unstemmed | Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery |
title_short | Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery |
title_sort | tropism of the novel aavbr1 capsid following subretinal delivery |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317317/ https://www.ncbi.nlm.nih.gov/pubmed/35887086 http://dx.doi.org/10.3390/ijms23147738 |
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