Focused ultrasound-mediated brain genome editing

Lao, Yeh‐Hsing; Ji, Robin; Zhou, Joyce K.; Snow, Kathy J.; Kwon, Nancy; Saville, Ethan; He, Siyu; Chauhan, Shradha; Chi, Chun‐Wei; Datta, Malika S; Zhang, Hairong; Li, Mingqiang; Gaitan, Yaned; Bechtel, Lawrence; Wu, Shih-Ying; Lutz, Cathleen; Tomer, Raju; Murray, Stephen A.; Chavez, Alejandro; Konofagou, Elisa E.; Leong, Kam W.

doi:10.1101/2022.12.10.519924

Cited by 1 publication

(1 citation statement)

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“…Gene editing is a promising technique for treating neurodegenerative disorders. Gene editing agents, such as CRISPR 43 , or Cre-recombinase 44 can be delivered to specific areas of the brain and have recently been tested through direct intracranial injection 22 or FUS-BBBO 33,45 . We investigated whether targeting large brain volumes for gene editing would also be feasible with FUS-BBBO.…”

Section: Resultsmentioning

confidence: 99%

Acoustically Targeted Noninvasive Gene Therapy in Large Brain Regions

Nouraein

Saenz

Mundo

et al. 2023

Preprint

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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. FUS-BBBO-based gene delivery also leads to a significant loss of neurons at the targeted sites. Overall, this study provides a brain-wide map of transduction efficiency and the first example of multi-site gene editing after noninvasive gene delivery with FUS-BBBO.

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