Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery
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...
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| Veröffentlicht in: | Scientific reports 2021-01, Vol.11 (1), p.1934, Article 1934 |
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| creator | Weber-Adrian, Danielle Kofoed, Rikke Hahn Silburt, Joseph Noroozian, Zeinab Shah, Kairavi Burgess, Alison Rideout, Shawna Kügler, Sebastian Hynynen, Kullervo Aubert, Isabelle |
| description | 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. |
| doi_str_mv | 10.1038/s41598-021-81046-5 |
| format | Article |
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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. 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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. 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chemistry</topic><topic>Synapsins - pharmacology</topic><topic>Tissue Distribution</topic><topic>Transduction, Genetic</topic><topic>Ultrasonic imaging</topic><topic>Ultrasonography</topic><topic>Ultrasound</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weber-Adrian, Danielle</creatorcontrib><creatorcontrib>Kofoed, Rikke Hahn</creatorcontrib><creatorcontrib>Silburt, Joseph</creatorcontrib><creatorcontrib>Noroozian, Zeinab</creatorcontrib><creatorcontrib>Shah, Kairavi</creatorcontrib><creatorcontrib>Burgess, Alison</creatorcontrib><creatorcontrib>Rideout, Shawna</creatorcontrib><creatorcontrib>Kügler, Sebastian</creatorcontrib><creatorcontrib>Hynynen, Kullervo</creatorcontrib><creatorcontrib>Aubert, Isabelle</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weber-Adrian, Danielle</au><au>Kofoed, Rikke Hahn</au><au>Silburt, Joseph</au><au>Noroozian, Zeinab</au><au>Shah, Kairavi</au><au>Burgess, Alison</au><au>Rideout, Shawna</au><au>Kügler, Sebastian</au><au>Hynynen, Kullervo</au><au>Aubert, Isabelle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Systemic AAV6-synapsin-GFP administration results in lower liver biodistribution, compared to AAV1&2 and AAV9, with neuronal expression following ultrasound-mediated brain delivery</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2021-01-21</date><risdate>2021</risdate><volume>11</volume><issue>1</issue><spage>1934</spage><pages>1934-</pages><artnum>1934</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33479314</pmid><doi>10.1038/s41598-021-81046-5</doi><orcidid>https://orcid.org/0000-0003-0177-0739</orcidid><orcidid>https://orcid.org/0000-0001-6219-2982</orcidid><orcidid>https://orcid.org/0000-0001-5163-9961</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/378/1341 631/378/340 Animals Blood-brain barrier Blood-Brain Barrier - drug effects Brain - diagnostic imaging Brain - drug effects Brain - metabolism Dependovirus - genetics Gene transfer Genetic Therapy Genetic Vectors - therapeutic use Green fluorescent protein Green Fluorescent Proteins - chemistry Green Fluorescent Proteins - pharmacology Hippocampus Humanities and Social Sciences Humans Injection Injections, Intravenous Intravenous administration Liver Liver - diagnostic imaging Liver - drug effects Magnetic Resonance Imaging Mice multidisciplinary Neostriatum Neurons - drug effects Promoter Regions, Genetic Science Science (multidisciplinary) Serotypes Synapsin Synapsins - chemistry Synapsins - pharmacology Tissue Distribution Transduction, Genetic Ultrasonic imaging Ultrasonography Ultrasound |
| 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 |
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