Focused ultrasound-mediated brain genome editing.

Gene editing in the brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches mainly rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To demonstrate that focused ultrasound can transiently open the blood–brain barrier to enable safe and effective intravenous delivery of CRISPR/Cas9 for gene editing in the brain.

Animal model / Human subject Adult male and female C57BL/6, Ai9, and TLR2 mice

Disease model Healthy

MRI or image guidance method Real-time cavitation monitoring

Targeted brain region(s) Targeted Hemisphere

Cargo name and characteristics AAV9/SaCas9 vectors encoding CRISPR/Cas9 machinery

Route of administration Intravenous

Outcomes and Safety

Summary of Outcomes FUS-mediated BBB opening enabled the effective delivery of intravenously administered AAV9/SaCas9 vectors to the brain, resulting in >5% overall gene editing efficiency. The FUS array system significantly enhanced vector disposition and editing compared to systemic delivery alone.

Duration of biological effect 3 weeks

Safety-related matter The authors note the technique is a safe alternative to direct intracranial injection, with no specific adverse effects reported in this brief communication.

Brain Region

Ultrasound Parameters

Ultrasound instrument Spherical single-element FUS transducer and P4-1 transducer array

FUS Mode pulsed

Treatment frequency Single session

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