title: Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound.
abstract: Recombinant adeno-associated viral (rAAV) vectors are potentially powerful tools for gene therapy of CNS diseases, but their penetration into brain parenchyma is severely limited by the blood-brain barrier (BBB) and current delivery relies on invasive stereotactic injection. Here we evaluate the local, targeted delivery of rAAV vectors into the brains of mice by noninvasive, reversible, microbubble-facilitated focused ultrasound (FUS), resulting in BBB opening that can be monitored and controlled by magnetic resonance imaging (MRI). Using this method, we found that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (1×10(9) vg/g) can successfully penetrate the BBB-opened brain regions to express GFP. We show that MRI monitoring of BBB-opening could serve as an indicator of the scale and distribution of AAV transduction. Transduction peaked at 3 weeks and neurons and astrocytes were affected. This novel, noninvasive delivery approach could significantly broaden the application of AAV-viral-vector-based genes for treatment of CNS diseases.
authors: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan.
authors: Po-Hung
authors: PH
authors: Hsu
authors: Kuo-Chen
authors: KC
authors: Wei
authors: Chiung-Yin
authors: CY
authors: Huang
authors: Chih-Jen
authors: CJ
authors: Wen
authors: Tzu-Chen
authors: TC
authors: Yen
authors: Chao-Lin
authors: CL
authors: Liu
authors: Ya-Tin
authors: YT
authors: Lin
authors: Jin-Chung
authors: JC
authors: Chen
authors: Chia-Rui
authors: CR
authors: Shen
authors: Hao-Li
authors: HL
authors: Liu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D003287:Contrast Media; D000229:Dependovirus / Q000235:genetics; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D045423:Microbubbles; D015203:Reproducibility of Results; D014161:Transduction, Genetic; D014465:Ultrasonics / Q000379:methods*
chemical_list: D003287:Contrast Media; D049452:Green Fluorescent Proteins