MRI-Guided Focused Ultrasound for Targeted Delivery of RAAV to the Brain

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2019 Feb 21

PMID 30783974

Citations 31

Authors

Zeinab Noroozian

Kristiana Xhima

Yuexi Huang

Brian K Kaspar

Sebastian Kugler

Kullervo Hynynen

Isabelle Aubert

Affiliations

Soon will be listed here.

Abstract

Recombinant adeno-associated viral (rAAV) vectors are a promising tool for therapeutic gene delivery to the brain. However, the delivery of rAAVs across the blood-brain barrier (BBB) and entry into the brain remains a major challenge for rAAV-based gene therapy. To circumvent this limitation, transcranial MRI-guided focused ultrasound (MRIgFUS) combined with intravenously injected microbubbles has been used to transiently and reversibly increase BBB permeability in targeted brain regions. Systemic administration of rAAVs at the time of sonication with focused ultrasound (FUS) facilitates the passage of rAAVs through the BBB and into the brain parenchyma. We and others have demonstrated that FUS-mediated rAAV delivery to the brain results in efficient transduction and transgene expression in vivo. Using this approach, the dose of intravenously injected rAAV variants that can cross the BBB can be reduced by 100 times, achieving significant transgene expression in the brain parenchyma with reduced peripheral transduction. Moreover, this strategy can be used to deliver rAAV variants that do not cross the BBB from the blood to selected brain regions. Here, we provide a detailed protocol for FUS-induced BBB permeability for targeted rAAV delivery to the brain of adult mice and rats.

Citing Articles

Focused Ultrasound-Mediated Disruption of the Blood-Brain Barrier for AAV9 Delivery in a Mouse Model of Huntington's Disease.

Owusu-Yaw B, Zhang Y, Garrett L, Yao A, Shing K, Batista A Pharmaceutics. 2024; 16(6).

PMID: 38931834 PMC: 11206648. DOI: 10.3390/pharmaceutics16060710.

How modern treatments have modified the role of surgery in pediatric low-grade glioma.

Boop S, Shimony N, Boop F Childs Nerv Syst. 2024; 40(10):3357-3365.

PMID: 38676718 PMC: 11511694. DOI: 10.1007/s00381-024-06412-w.

Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies.

Tong H, Yang T, Xu S, Li X, Liu L, Zhou G Int J Mol Sci. 2024; 25(7).

PMID: 38612657 PMC: 11011923. DOI: 10.3390/ijms25073845.

Glioblastoma Therapy: Past, Present and Future.

Obrador E, Moreno-Murciano P, Oriol-Caballo M, Lopez-Blanch R, Pineda B, Gutierrez-Arroyo J Int J Mol Sci. 2024; 25(5).

PMID: 38473776 PMC: 10931797. DOI: 10.3390/ijms25052529.

Drug Delivery to the Brain: Recent Advances and Unmet Challenges.

Bhunia S, Kolishetti N, Vashist A, Arias A, Brooks D, Nair M Pharmaceutics. 2023; 15(12).

PMID: 38139999 PMC: 10747851. DOI: 10.3390/pharmaceutics15122658.

References

Costantini L, Bakowska J, Breakefield X, Isacson O . Gene therapy in the CNS. Gene Ther. 2000; 7(2):93-109. DOI: 10.1038/sj.gt.3301119. View

Diehl K, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D . A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol. 2001; 21(1):15-23. DOI: 10.1002/jat.727. View

Hynynen K, McDannold N, Vykhodtseva N, Jolesz F . Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001; 220(3):640-6. DOI: 10.1148/radiol.2202001804. View

McDannold N, Vykhodtseva N, Hynynen K . Use of ultrasound pulses combined with Definity for targeted blood-brain barrier disruption: a feasibility study. Ultrasound Med Biol. 2007; 33(4):584-90. PMC: 2066193. DOI: 10.1016/j.ultrasmedbio.2006.10.004. View

Treat L, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K . Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer. 2007; 121(4):901-7. DOI: 10.1002/ijc.22732. View

Sheikov N, McDannold N, Sharma S, Hynynen K . Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008; 34(7):1093-104. PMC: 2518085. DOI: 10.1016/j.ultrasmedbio.2007.12.015. View

Zincarelli C, Soltys S, Rengo G, Rabinowitz J . Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol Ther. 2008; 16(6):1073-80. DOI: 10.1038/mt.2008.76. View

Foust K, Nurre E, Montgomery C, Hernandez A, Chan C, Kaspar B . Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2008; 27(1):59-65. PMC: 2895694. DOI: 10.1038/nbt.1515. View

Manfredsson F, Rising A, Mandel R . AAV9: a potential blood-brain barrier buster. Mol Ther. 2009; 17(3):403-5. PMC: 2835088. DOI: 10.1038/mt.2009.15. View

10.

Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar A . Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther. 2009; 17(7):1187-96. PMC: 2835208. DOI: 10.1038/mt.2009.71. View

11.

Chopra R, Curiel L, Staruch R, Morrison L, Hynynen K . An MRI-compatible system for focused ultrasound experiments in small animal models. Med Phys. 2009; 36(5):1867-74. PMC: 2736709. DOI: 10.1118/1.3115680. View

12.

Lim S, Airavaara M, Harvey B . Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol Res. 2009; 61(1):14-26. PMC: 2880921. DOI: 10.1016/j.phrs.2009.10.002. View

13.

Mason M, Ehlert E, Eggers R, Pool C, Hermening S, Huseinovic A . Comparison of AAV serotypes for gene delivery to dorsal root ganglion neurons. Mol Ther. 2010; 18(4):715-24. PMC: 2862541. DOI: 10.1038/mt.2010.19. View

14.

Foust K, Wang X, McGovern V, Braun L, Bevan A, Haidet A . Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010; 28(3):271-4. PMC: 2889698. DOI: 10.1038/nbt.1610. View

15.

Mullin L, Gessner R, Kwan J, Kaya M, Borden M, Dayton P . Effect of anesthesia carrier gas on in vivo circulation times of ultrasound microbubble contrast agents in rats. Contrast Media Mol Imaging. 2011; 6(3):126-31. PMC: 3341737. DOI: 10.1002/cmmi.414. View

16.

Huang Y, Hynynen K . MR-guided focused ultrasound for brain ablation and blood-brain barrier disruption. Methods Mol Biol. 2011; 711:579-93. DOI: 10.1007/978-1-61737-992-5_30. View

17.

Itani M, Mattrey R . The effect of inhaled gases on ultrasound contrast agent longevity in vivo. Mol Imaging Biol. 2011; 14(1):40-6. PMC: 3258392. DOI: 10.1007/s11307-011-0475-5. View

18.

Gray S, Matagne V, Bachaboina L, Yadav S, Ojeda S, Samulski R . Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther. 2011; 19(6):1058-69. PMC: 3129805. DOI: 10.1038/mt.2011.72. View

19.

Forsayeth J, Bankiewicz K . AAV9: over the fence and into the woods . . . Mol Ther. 2011; 19(6):1006-7. PMC: 3129793. DOI: 10.1038/mt.2011.95. View

20.

McDannold N, Zhang Y, Vykhodtseva N . Blood-brain barrier disruption and vascular damage induced by ultrasound bursts combined with microbubbles can be influenced by choice of anesthesia protocol. Ultrasound Med Biol. 2011; 37(8):1259-70. PMC: 3129385. DOI: 10.1016/j.ultrasmedbio.2011.04.019. View