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New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets

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New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets. / Giannelli, Serena Gea; Luoni, Mirko; Iannielli, Angelo; Middeldorp, Jinte; Philippens, Ingrid; Bido, Simone; Körbelin, Jakob; Broccoli, Vania.

in: ISCIENCE, Jahrgang 27, Nr. 5, 17.05.2024, S. 109777.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Giannelli, SG, Luoni, M, Iannielli, A, Middeldorp, J, Philippens, I, Bido, S, Körbelin, J & Broccoli, V 2024, 'New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets', ISCIENCE, Jg. 27, Nr. 5, S. 109777. https://doi.org/10.1016/j.isci.2024.109777

APA

Giannelli, S. G., Luoni, M., Iannielli, A., Middeldorp, J., Philippens, I., Bido, S., Körbelin, J., & Broccoli, V. (2024). New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets. ISCIENCE, 27(5), 109777. https://doi.org/10.1016/j.isci.2024.109777

Vancouver

Giannelli SG, Luoni M, Iannielli A, Middeldorp J, Philippens I, Bido S et al. New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets. ISCIENCE. 2024 Mai 17;27(5):109777. https://doi.org/10.1016/j.isci.2024.109777

Bibtex

@article{832ea51fcffb476fa3291fb1cd82bdf8,
title = "New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets",
abstract = "Although adeno-associated virus 9 (AAV9) has been highly exploited as delivery platform for gene-based therapies, its efficacy is hampered by low efficiency in crossing the adult blood-brain barrier (BBB) and pronounced targeting to the liver upon intravenous delivery. We generated a new galactose binding-deficient AAV9 peptide display library and selected two new AAV9 engineered capsids with enhanced targeting in mouse and marmoset brains after intravenous delivery. Interestingly, the loss of galactose binding greatly reduced undesired targeting to peripheral organs, particularly the liver, while not compromising transduction of the brain vasculature. However, the galactose binding was necessary to efficiently infect non-endothelial brain cells. Thus, the combinatorial actions of the galactose-binding domain and the incorporated displayed peptide are crucial to enhance BBB crossing along with brain cell transduction. This study describes two novel capsids with high brain endothelial infectivity and extremely low liver targeting based on manipulating the AAV9 galactose-binding domain.",
author = "Giannelli, {Serena Gea} and Mirko Luoni and Angelo Iannielli and Jinte Middeldorp and Ingrid Philippens and Simone Bido and Jakob K{\"o}rbelin and Vania Broccoli",
note = "{\textcopyright} 2024 The Author(s).",
year = "2024",
month = may,
day = "17",
doi = "10.1016/j.isci.2024.109777",
language = "English",
volume = "27",
pages = "109777",
journal = "ISCIENCE",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets

AU - Giannelli, Serena Gea

AU - Luoni, Mirko

AU - Iannielli, Angelo

AU - Middeldorp, Jinte

AU - Philippens, Ingrid

AU - Bido, Simone

AU - Körbelin, Jakob

AU - Broccoli, Vania

N1 - © 2024 The Author(s).

PY - 2024/5/17

Y1 - 2024/5/17

N2 - Although adeno-associated virus 9 (AAV9) has been highly exploited as delivery platform for gene-based therapies, its efficacy is hampered by low efficiency in crossing the adult blood-brain barrier (BBB) and pronounced targeting to the liver upon intravenous delivery. We generated a new galactose binding-deficient AAV9 peptide display library and selected two new AAV9 engineered capsids with enhanced targeting in mouse and marmoset brains after intravenous delivery. Interestingly, the loss of galactose binding greatly reduced undesired targeting to peripheral organs, particularly the liver, while not compromising transduction of the brain vasculature. However, the galactose binding was necessary to efficiently infect non-endothelial brain cells. Thus, the combinatorial actions of the galactose-binding domain and the incorporated displayed peptide are crucial to enhance BBB crossing along with brain cell transduction. This study describes two novel capsids with high brain endothelial infectivity and extremely low liver targeting based on manipulating the AAV9 galactose-binding domain.

AB - Although adeno-associated virus 9 (AAV9) has been highly exploited as delivery platform for gene-based therapies, its efficacy is hampered by low efficiency in crossing the adult blood-brain barrier (BBB) and pronounced targeting to the liver upon intravenous delivery. We generated a new galactose binding-deficient AAV9 peptide display library and selected two new AAV9 engineered capsids with enhanced targeting in mouse and marmoset brains after intravenous delivery. Interestingly, the loss of galactose binding greatly reduced undesired targeting to peripheral organs, particularly the liver, while not compromising transduction of the brain vasculature. However, the galactose binding was necessary to efficiently infect non-endothelial brain cells. Thus, the combinatorial actions of the galactose-binding domain and the incorporated displayed peptide are crucial to enhance BBB crossing along with brain cell transduction. This study describes two novel capsids with high brain endothelial infectivity and extremely low liver targeting based on manipulating the AAV9 galactose-binding domain.

U2 - 10.1016/j.isci.2024.109777

DO - 10.1016/j.isci.2024.109777

M3 - SCORING: Journal article

C2 - 38711458

VL - 27

SP - 109777

JO - ISCIENCE

JF - ISCIENCE

SN - 2589-0042

IS - 5

ER -