The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites
Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), which facilitates the entry of intravenously administered adeno-associated viruses (AAVs) from the blood to t...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S232905012200136X |
| _version_ | 1798020444336422912 |
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| author | Rikke Hahn Kofoed Kate Noseworthy Kathleen Wu Shuruthisai Sivadas Lisa Stanek Bradford Elmer Kullervo Hynynen Lamya S. Shihabuddin Isabelle Aubert |
| author_facet | Rikke Hahn Kofoed Kate Noseworthy Kathleen Wu Shuruthisai Sivadas Lisa Stanek Bradford Elmer Kullervo Hynynen Lamya S. Shihabuddin Isabelle Aubert |
| author_sort | Rikke Hahn Kofoed |
| collection | DOAJ |
| description | Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), which facilitates the entry of intravenously administered adeno-associated viruses (AAVs) from the blood to targeted brain areas. To date, the properties of the AAVs used for MRIgFUS delivery resulted in cell transduction limited to MRIgFUS-targeted sites. Considering future clinical applications, strategies are needed to deliver genes to multiple locations and large brain volumes while creating minimal BBB modulation. Here we combine MRIgFUS with a vector that has enhanced biodistribution following brain entry, AAV2-HBKO, to mediate broad gene delivery to targeted brain regions at levels with potential therapeutic relevance. Expression of a reporter gene was achieved in 13% and 21% of all neurons present in the striatum and thalamus, respectively, while targeting only 28% of the brain regions with MRIgFUS. Compared with AAV9, MRIgFUS-mediated delivery of AAV2-HBKO showed greater diffusion in the brain and a higher percentage of the neurons expressing the transgene. MRIgFUS AAV2-HBKO gene delivery to the brain has the potential to reach levels that are functionally and clinically relevant, and this even when using relatively low intravenous AAV dosages, compared with what is currently used in clinical trials. |
| first_indexed | 2024-04-11T16:57:36Z |
| format | Article |
| id | doaj.art-279dc757e6004b4ea517cfc14340221c |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-11T16:57:36Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-279dc757e6004b4ea517cfc14340221c2022-12-22T04:13:13ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-12-0127167184The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sitesRikke Hahn Kofoed0Kate Noseworthy1Kathleen Wu2Shuruthisai Sivadas3Lisa Stanek4Bradford Elmer5Kullervo Hynynen6Lamya S. Shihabuddin7Isabelle Aubert8Biological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Temerty Faculty of Medicine, 1 King’s College Cir., Toronto, ON M5S 1A8, Canada; Corresponding author Rikke Hahn Kofoed, Biological Sciences, Sunnybrook Research Institute, Hurvitz Brain Sciences Research Program, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada.Biological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Temerty Faculty of Medicine, 1 King’s College Cir., Toronto, ON M5S 1A8, CanadaBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON M4N 3M5, CanadaBiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON M4N 3M5, CanadaSanofi, 49 New York Ave., Framingham, MA 01701-9322, USASanofi, 49 New York Ave., Framingham, MA 01701-9322, USAPhysical Sciences, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Temerty Faculty of Medicine, 101 College Street, Toronto, ON M5G 1L7, CanadaSanofi, 49 New York Ave., Framingham, MA 01701-9322, USABiological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Temerty Faculty of Medicine, 1 King’s College Cir., Toronto, ON M5S 1A8, Canada; Corresponding author Isabelle Aubert, Biological Sciences, Sunnybrook Research Institute, Hurvitz Brain Sciences Research Program, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada.Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), which facilitates the entry of intravenously administered adeno-associated viruses (AAVs) from the blood to targeted brain areas. To date, the properties of the AAVs used for MRIgFUS delivery resulted in cell transduction limited to MRIgFUS-targeted sites. Considering future clinical applications, strategies are needed to deliver genes to multiple locations and large brain volumes while creating minimal BBB modulation. Here we combine MRIgFUS with a vector that has enhanced biodistribution following brain entry, AAV2-HBKO, to mediate broad gene delivery to targeted brain regions at levels with potential therapeutic relevance. Expression of a reporter gene was achieved in 13% and 21% of all neurons present in the striatum and thalamus, respectively, while targeting only 28% of the brain regions with MRIgFUS. Compared with AAV9, MRIgFUS-mediated delivery of AAV2-HBKO showed greater diffusion in the brain and a higher percentage of the neurons expressing the transgene. MRIgFUS AAV2-HBKO gene delivery to the brain has the potential to reach levels that are functionally and clinically relevant, and this even when using relatively low intravenous AAV dosages, compared with what is currently used in clinical trials.http://www.sciencedirect.com/science/article/pii/S232905012200136Xfocused ultrasoundmicrobubblesadeno-associated virusAAV2-HBKOblood-brain barriergene delivery |
| spellingShingle | Rikke Hahn Kofoed Kate Noseworthy Kathleen Wu Shuruthisai Sivadas Lisa Stanek Bradford Elmer Kullervo Hynynen Lamya S. Shihabuddin Isabelle Aubert The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites Molecular Therapy: Methods & Clinical Development focused ultrasound microbubbles adeno-associated virus AAV2-HBKO blood-brain barrier gene delivery |
| title | The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites |
| title_full | The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites |
| title_fullStr | The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites |
| title_full_unstemmed | The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites |
| title_short | The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites |
| title_sort | engineered aav2 hbko promotes non invasive gene delivery to large brain regions beyond ultrasound targeted sites |
| topic | focused ultrasound microbubbles adeno-associated virus AAV2-HBKO blood-brain barrier gene delivery |
| url | http://www.sciencedirect.com/science/article/pii/S232905012200136X |
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