Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery

Abstract Non-surgical gene delivery to the brain can be achieved following intravenous injection of viral vectors coupled with transcranial MRI-guided focused ultrasound (MRIgFUS) to temporarily and locally permeabilize the blood–brain barrier. Vector and promoter selection can provide neuronal expr...

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Autores principales:	Danielle Weber-Adrian, Rikke Hahn Kofoed, Joseph Silburt, Zeinab Noroozian, Kairavi Shah, Alison Burgess, Shawna Rideout, Sebastian Kügler, Kullervo Hynynen, Isabelle Aubert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4d292ee5b9e644b58491675946f97773
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spelling	oai:doaj.org-article:4d292ee5b9e644b58491675946f977732021-12-02T15:23:28ZSystemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery10.1038/s41598-021-81046-52045-2322https://doaj.org/article/4d292ee5b9e644b58491675946f977732021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81046-5https://doaj.org/toc/2045-2322Abstract Non-surgical gene delivery to the brain can be achieved following intravenous injection of viral vectors coupled with transcranial MRI-guided focused ultrasound (MRIgFUS) to temporarily and locally permeabilize the blood–brain barrier. Vector and promoter selection can provide neuronal expression in the brain, while limiting biodistribution and expression in peripheral organs. To date, the biodistribution of adeno-associated viruses (AAVs) within peripheral organs had not been quantified following intravenous injection and MRIgFUS delivery to the brain. We evaluated the quantity of viral DNA from the serotypes AAV9, AAV6, and a mosaic AAV1&2, expressing green fluorescent protein (GFP) under the neuron-specific synapsin promoter (syn). AAVs were administered intravenously during MRIgFUS targeting to the striatum and hippocampus in mice. The syn promoter led to undetectable levels of GFP expression in peripheral organs. In the liver, the biodistribution of AAV9 and AAV1&2 was 12.9- and 4.4-fold higher, respectively, compared to AAV6. The percentage of GFP-positive neurons in the FUS-targeted areas of the brain was comparable for AAV6-syn-GFP and AAV1&2-syn-GFP. In summary, MRIgFUS-mediated gene delivery with AAV6-syn-GFP had lower off-target biodistribution in the liver compared to AAV9 and AAV1&2, while providing neuronal GFP expression in the striatum and hippocampus.Danielle Weber-AdrianRikke Hahn KofoedJoseph SilburtZeinab NoroozianKairavi ShahAlison BurgessShawna RideoutSebastian KüglerKullervo HynynenIsabelle AubertNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Danielle Weber-Adrian Rikke Hahn Kofoed Joseph Silburt Zeinab Noroozian Kairavi Shah Alison Burgess Shawna Rideout Sebastian Kügler Kullervo Hynynen Isabelle Aubert Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
description	Abstract Non-surgical gene delivery to the brain can be achieved following intravenous injection of viral vectors coupled with transcranial MRI-guided focused ultrasound (MRIgFUS) to temporarily and locally permeabilize the blood–brain barrier. Vector and promoter selection can provide neuronal expression in the brain, while limiting biodistribution and expression in peripheral organs. To date, the biodistribution of adeno-associated viruses (AAVs) within peripheral organs had not been quantified following intravenous injection and MRIgFUS delivery to the brain. We evaluated the quantity of viral DNA from the serotypes AAV9, AAV6, and a mosaic AAV1&2, expressing green fluorescent protein (GFP) under the neuron-specific synapsin promoter (syn). AAVs were administered intravenously during MRIgFUS targeting to the striatum and hippocampus in mice. The syn promoter led to undetectable levels of GFP expression in peripheral organs. In the liver, the biodistribution of AAV9 and AAV1&2 was 12.9- and 4.4-fold higher, respectively, compared to AAV6. The percentage of GFP-positive neurons in the FUS-targeted areas of the brain was comparable for AAV6-syn-GFP and AAV1&2-syn-GFP. In summary, MRIgFUS-mediated gene delivery with AAV6-syn-GFP had lower off-target biodistribution in the liver compared to AAV9 and AAV1&2, while providing neuronal GFP expression in the striatum and hippocampus.
format	article
author	Danielle Weber-Adrian Rikke Hahn Kofoed Joseph Silburt Zeinab Noroozian Kairavi Shah Alison Burgess Shawna Rideout Sebastian Kügler Kullervo Hynynen Isabelle Aubert
author_facet	Danielle Weber-Adrian Rikke Hahn Kofoed Joseph Silburt Zeinab Noroozian Kairavi Shah Alison Burgess Shawna Rideout Sebastian Kügler Kullervo Hynynen Isabelle Aubert
author_sort	Danielle Weber-Adrian
title	Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
title_short	Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
title_full	Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
title_fullStr	Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
title_full_unstemmed	Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
title_sort	systemic aav6-synapsin-gfp administration results in lower liver biodistribution, compared to aav1&2 and aav9, with neuronal expression following ultrasound-mediated brain delivery
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4d292ee5b9e644b58491675946f97773
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Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery

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