Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases

Overview

Journal Front Neurol

Specialty Neurology

Date 2021 Nov 22

PMID 34803886

Citations 12

Authors

Paul S Fishman

Jonathan M Fischell

Affiliations

Soon will be listed here.

Abstract

The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.

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References

Hynynen K . Macromolecular delivery across the blood-brain barrier. Methods Mol Biol. 2008; 480:175-85. DOI: 10.1007/978-1-59745-429-2_13. View

Karakatsani M, Wang S, Samiotaki G, Kugelman T, Olumolade O, Acosta C . Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson's disease. J Control Release. 2019; 303:289-301. PMC: 6618306. DOI: 10.1016/j.jconrel.2019.03.030. View

Cockerill I, Oliver J, Xu H, Fu B, Zhu D . Blood-Brain Barrier Integrity and Clearance of Amyloid-β from the BBB. Adv Exp Med Biol. 2018; 1097:261-278. DOI: 10.1007/978-3-319-96445-4_14. View

Levites Y, Smithson L, Price R, Dakin R, Yuan B, Sierks M . Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J. 2006; 20(14):2576-8. DOI: 10.1096/fj.06-6463fje. View

Avgerinos K, Ferrucci L, Kapogiannis D . Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev. 2021; 68:101339. PMC: 8161699. DOI: 10.1016/j.arr.2021.101339. View

Lemon R . The Cortical "Upper Motoneuron" in Health and Disease. Brain Sci. 2021; 11(5). PMC: 8151778. DOI: 10.3390/brainsci11050619. View

Konofagou E, Tung Y, Choi J, Deffieux T, Baseri B, Vlachos F . Ultrasound-induced blood-brain barrier opening. Curr Pharm Biotechnol. 2011; 13(7):1332-45. PMC: 4038976. DOI: 10.2174/138920112800624364. View

Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I . Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology. 2014; 273(3):736-45. PMC: 4314115. DOI: 10.1148/radiol.14140245. View

OReilly M, Jones R, Barrett E, Schwab A, Head E, Hynynen K . Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging. Theranostics. 2017; 7(14):3573-3584. PMC: 5596444. DOI: 10.7150/thno.20621. View

10.

Mainprize T, Lipsman N, Huang Y, Meng Y, Bethune A, Ironside S . Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study. Sci Rep. 2019; 9(1):321. PMC: 6344541. DOI: 10.1038/s41598-018-36340-0. View

11.

Kobus T, Vykhodtseva N, Pilatou M, Zhang Y, McDannold N . Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound. Ultrasound Med Biol. 2015; 42(2):481-92. PMC: 4816071. DOI: 10.1016/j.ultrasmedbio.2015.10.009. View

12.

Pardridge W, Boado R . Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 2012; 503:269-92. DOI: 10.1016/B978-0-12-396962-0.00011-2. View

13.

Jordao J, Thevenot E, Markham-Coultes K, Scarcelli T, Weng Y, Xhima K . Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol. 2013; 248:16-29. PMC: 4000699. DOI: 10.1016/j.expneurol.2013.05.008. View

14.

Dubey S, Heinen S, Krantic S, McLaurin J, Branch D, Hynynen K . Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2020; 117(51):32691-32700. PMC: 7768694. DOI: 10.1073/pnas.1908658117. View

15.

Kimura S, Harashima H . Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB. Pharmaceutics. 2020; 12(12). PMC: 7765480. DOI: 10.3390/pharmaceutics12121216. View

16.

Mead B, Kim N, Miller G, Hodges D, Mastorakos P, Klibanov A . Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model. Nano Lett. 2017; 17(6):3533-3542. PMC: 5539956. DOI: 10.1021/acs.nanolett.7b00616. View

17.

Jordao J, Ayala-Grosso C, Markham K, Huang Y, Chopra R, McLaurin J . Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease. PLoS One. 2010; 5(5):e10549. PMC: 2868024. DOI: 10.1371/journal.pone.0010549. View

18.

Lin C, Hsieh H, Chen C, Wu S, Tsai C, Huang C . Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson's disease mouse model. J Control Release. 2016; 235:72-81. DOI: 10.1016/j.jconrel.2016.05.052. View

19.

Hitti F, Yang A, Gonzalez-Alegre P, Baltuch G . Human gene therapy approaches for the treatment of Parkinson's disease: An overview of current and completed clinical trials. Parkinsonism Relat Disord. 2019; 66:16-24. DOI: 10.1016/j.parkreldis.2019.07.018. View

20.

Kinoshita M, McDannold N, Jolesz F, Hynynen K . Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006; 103(31):11719-23. PMC: 1544236. DOI: 10.1073/pnas.0604318103. View