School of Medicine Publications and Presentations
Document Type
Article
Publication Date
8-12-2024
Abstract
Gene therapy using a protein-based CRISPR system in the brain has practical limitations due to current delivery systems, especially in the presence of arterial occlusion. To overcome these obstacles and improve stability, we designed a system for intranasal administration of gene therapy for the treatment of ischemic stroke.
Methods: Nanoparticles containing the protein-based CRISPR/dCas9 system targeting Sirt1 were delivered intranasally to the brain in a mouse model of ischemic stroke. The CRISPR/dCas9 system was encapsulated with calcium phosphate (CaP) nanoparticles to prevent them from being degraded. They were then conjugated with β-hydroxybutyrates (bHb) to target monocarboxylic acid transporter 1 (MCT1) in nasal epithelial cells to facilitate their transfer into the brain.
Results: Human nasal epithelial cells were shown to uptake and transfer nanoparticles to human brain endothelial cells with high efficiency in vitro. The intranasal administration of the dCas9/CaP/PEI-PEG-bHb nanoparticles in mice effectively upregulated the target gene, Sirt1, in the brain, decreased cerebral edema and increased survival after permanent middle cerebral artery occlusion. Additionally, we observed no significant in vivo toxicity associated with intranasal administration of the nanoparticles, highlighting the safety of this approach.
Conclusion: This study demonstrates that the proposed protein-based CRISPR-dCas9 system targeting neuroprotective genes in general, and SIRT1 in particular, can be a potential novel therapy for acute ischemic stroke.
Recommended Citation
Ryu, J. Y., Cerecedo-Lopez, C., Yang, H., Ryu, I., & Du, R. (2024). Brain-targeted intranasal delivery of protein-based gene therapy for treatment of ischemic stroke. Theranostics, 14(12), 4773–4786. https://doi.org/10.7150/thno.98088
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
First Page
4773
Last Page
4786
Publication Title
Theranostics
DOI
https://doi.org/10.7150/thno.98088
Academic Level
faculty
Mentor/PI Department
Surgery
Comments
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