Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3
Background Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and micro...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Drug Delivery |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/10717544.2022.2035855 |
| _version_ | 1828414142127538176 |
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| author | Dennison Trinh Joanne Nash David Goertz Kullervo Hynynen Sharshi Bulner Umar Iqbal James Keenan |
| author_facet | Dennison Trinh Joanne Nash David Goertz Kullervo Hynynen Sharshi Bulner Umar Iqbal James Keenan |
| author_sort | Dennison Trinh |
| collection | DOAJ |
| description | Background Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically.Methods We developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.SIRT3-myc [adeno-associated virus expressing myc-tagged SIRT3], which has previously been shown to have disease modifying effects in animal models of Parkinson’s disease (PD). The lipid shells of the perfluorocarbon gas MDCs were covalently conjugated to antibodies with binding specificity to AAVs. Following systemic (iv) delivery of AAV.SIRT3-myc MDCs, MR-g-FUS was used to deliver SIRT3-myc to brain regions affected in PD. SIRT3-myc expression was determined post mortem, using immunohistochemistry.Results An in vitro, SH-SY5Y cell culture model was used to show that the localized destruction of MDCs using ultrasound exposures within biological safety limits dissociated AAV2-GFP (green fluorescent protein) from the MDCs in the targeted area while maintaining their transduction capacity. In rats, MR-g-FUS resulted in BBB permeabilization in the striatum and substantia nigra (SNc). SIRT3-myc was expressed in the striatum, but not the SNc.Conclusion These studies demonstrate that MDCs combined with MR-g-FUS are an effective method for delivery of viral vector gene therapies, such as AAV.SIRT3, to brain regions affected in PD. This technology may prove useful as a disease-modifying strategy in PD and other neurodegenerative disorders. |
| first_indexed | 2024-12-10T13:21:57Z |
| format | Article |
| id | doaj.art-829924003aa94284a5e1c9a07761be4d |
| institution | Directory Open Access Journal |
| issn | 1071-7544 1521-0464 |
| language | English |
| last_indexed | 2024-12-10T13:21:57Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Drug Delivery |
| spelling | doaj.art-829924003aa94284a5e1c9a07761be4d2022-12-22T01:47:18ZengTaylor & Francis GroupDrug Delivery1071-75441521-04642022-12-012911176118310.1080/10717544.2022.2035855Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3Dennison Trinh0Joanne Nash1David Goertz2Kullervo Hynynen3Sharshi Bulner4Umar Iqbal5James Keenan6Department of Biological Sciences, University of Toronto at Scarborough, Scarborough, CanadaDepartment of Biological Sciences, University of Toronto at Scarborough, Scarborough, CanadaSunnybrook Research Institute, Toronto, CanadaSunnybrook Research Institute, Toronto, CanadaSunnybrook Research Institute, Toronto, CanadaHuman Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, CanadaArtenga Inc, Ottawa, CanadaBackground Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically.Methods We developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.SIRT3-myc [adeno-associated virus expressing myc-tagged SIRT3], which has previously been shown to have disease modifying effects in animal models of Parkinson’s disease (PD). The lipid shells of the perfluorocarbon gas MDCs were covalently conjugated to antibodies with binding specificity to AAVs. Following systemic (iv) delivery of AAV.SIRT3-myc MDCs, MR-g-FUS was used to deliver SIRT3-myc to brain regions affected in PD. SIRT3-myc expression was determined post mortem, using immunohistochemistry.Results An in vitro, SH-SY5Y cell culture model was used to show that the localized destruction of MDCs using ultrasound exposures within biological safety limits dissociated AAV2-GFP (green fluorescent protein) from the MDCs in the targeted area while maintaining their transduction capacity. In rats, MR-g-FUS resulted in BBB permeabilization in the striatum and substantia nigra (SNc). SIRT3-myc was expressed in the striatum, but not the SNc.Conclusion These studies demonstrate that MDCs combined with MR-g-FUS are an effective method for delivery of viral vector gene therapies, such as AAV.SIRT3, to brain regions affected in PD. This technology may prove useful as a disease-modifying strategy in PD and other neurodegenerative disorders.https://www.tandfonline.com/doi/10.1080/10717544.2022.2035855Focused ultrasoundmicrobubblesBBB drug deliverySirtuin3SIRT3Parkinson’s |
| spellingShingle | Dennison Trinh Joanne Nash David Goertz Kullervo Hynynen Sharshi Bulner Umar Iqbal James Keenan Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 Drug Delivery Focused ultrasound microbubbles BBB drug delivery Sirtuin3 SIRT3 Parkinson’s |
| title | Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 |
| title_full | Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 |
| title_fullStr | Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 |
| title_full_unstemmed | Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 |
| title_short | Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 |
| title_sort | microbubble drug conjugate and focused ultrasound blood brain barrier delivery of aav 2 sirt 3 |
| topic | Focused ultrasound microbubbles BBB drug delivery Sirtuin3 SIRT3 Parkinson’s |
| url | https://www.tandfonline.com/doi/10.1080/10717544.2022.2035855 |
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