| Téléchargement | - Voir la version finale : Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3 (PDF, 1.8 Mio)
|
|---|
| DOI | Trouver le DOI : https://doi.org/10.1080/10717544.2022.2035855 |
|---|
| Auteur | Rechercher : Trinh, Dennison1; Rechercher : Nash, Joanne1; Rechercher : Goertz, David2, 3; Rechercher : Hynynen, Kullervo2, 3; Rechercher : Bulner, Sharshi2; Rechercher : Iqbal, Umar4, 5; Rechercher : Keenan, James6 |
|---|
| Affiliation | - Department of Biological Sciences, University of Toronto at Scarborough, Scarborough, Canada
- Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Conseil national de recherches Canada. Thérapeutique en santé humaine
- Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, Canada
- Artenga Inc, Ottawa, Canada
|
|---|
| Bailleur de fonds | Rechercher : The Focused Ultrasound Foundation |
|---|
| Format | Texte, Article |
|---|
| Sujet | BBB drug delivery; focused ultrasound; microbubbles; parkinson's; SIRT3; Sirtuin3 |
|---|
| Résumé | 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. |
|---|
| Date de publication | 2022-12-31 |
|---|
| Maison d’édition | Elsevier |
|---|
| Licence | |
|---|
| Dans | |
|---|
| Langue | anglais |
|---|
| Publications évaluées par des pairs | Oui |
|---|
| Exporter la notice | Exporter en format RIS |
|---|
| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
|---|
| Identificateur de l’enregistrement | 823fbff4-9d46-4876-9812-a88eb205d32a |
|---|
| Enregistrement créé | 2024-02-27 |
|---|
| Enregistrement modifié | 2024-02-27 |
|---|
