RT Journal Article
SR Electronic
T1 Acoustically Targeted Noninvasive Gene Therapy in Large Brain Regions
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.19.524626
DO 10.1101/2023.01.19.524626
A1 Shirin Nouraein
A1 Sangsin Lee
A1 Vidal A. Saenz
A1 Huckie C. Del Mundo
A1 Joycelyn Yiu
A1 Jerzy O. Szablowski
YR 2023
UL http://biorxiv.org/content/early/2023/01/20/2023.01.19.524626.abstract
AB Focused Ultrasound Blood-Brain Barrier Opening (FUS-BBBO) can deliver adeno-associated viral vectors (AAVs) to treat genetic disorders of the brain. However, such disorders often affect large brain regions. Moreover, the applicability of FUS-BBBO in the treatment of brain-wide genetic disorders has not yet been evaluated. Herein, we evaluated the transduction efficiency and safety of opening up to 105 sites simultaneously. Increasing the number of targeted sites increased gene delivery efficiency at each site. We achieved transduction of up to 60% of brain cells with comparable efficiency in the majority of the brain regions. Furthermore, gene delivery with FUS-BBBO was safe even when all 105 sites were targeted simultaneously without negative effects on animal weight, neuronal loss, or astrocyte activation. To evaluate the application of multi-site FUS-BBBO for gene therapy, we used it for gene editing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, and found effective gene editing, but also a loss of neurons at the targeted sites. Overall, this study provides a brain-wide map of transduction efficiency and the first example of gene editing after site-specific noninvasive gene delivery to a large brain region.Competing Interest StatementThe authors have declared no competing interest.