A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Joanna M Wasielewska; Juliana C S Chaves; Rebecca L Johnston; Laura A Milton; Damián Hernández; Liyu Chen; Jae Song; Wendy Lee; Gerhard Leinenga; Rebecca M Nisbet; Alice Pébay; Jürgen Götz; Anthony R White; Lotta E Oikari

doi:10.7150/thno.72685

A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Theranostics. 2022 Sep 25;12(16):6826-6847. doi: 10.7150/thno.72685. eCollection 2022.

Authors

Joanna M Wasielewska^{1

2}, Juliana C S Chaves¹, Rebecca L Johnston³, Laura A Milton¹, Damián Hernández⁴, Liyu Chen⁵, Jae Song⁵, Wendy Lee⁵, Gerhard Leinenga⁵, Rebecca M Nisbet⁶, Alice Pébay^{4

7}, Jürgen Götz⁵, Anthony R White^{1

8}, Lotta E Oikari¹

Affiliations

¹ Cell & Molecular Biology Department, Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute; Brisbane, QLD, Australia.
² Faculty of Medicine, The University of Queensland; Brisbane, QLD, Australia.
³ Genetics & Computational Biology Department, QIMR Berghofer Medical Research Institute; Brisbane, QLD, Australia.
⁴ Department of Anatomy and Physiology, The University of Melbourne; Parkville, VIC, Australia.
⁵ Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland; Brisbane, QLD, Australia.
⁶ The Florey Institute of Neuroscience and Mental Health; Parkville, VIC, Australia.
⁷ Department of Surgery, Royal Melbourne Hospital, The University of Melbourne; Parkville, VIC, Australia.
⁸ School of Biomedical Sciences, Faculty of Medicine, The University of Queensland; Brisbane, QLD, Australia.

Abstract

Rationale: The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles (FUS^+MB) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS^+MB is safe, however, the effects of FUS^+MB on human BBB cells, especially in the context of AD, remain sparsely investigated. In addition, there currently are no cell platforms to test for FUS^+MB-mediated drug delivery. Methods: Here we generated BBB cells (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high sporadic AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We established mono- and co-culture models of human sporadic AD and control BBB cells to investigate the effects of FUS^+MB on BBB cell phenotype and to screen for the delivery of two potentially therapeutic AD antibodies, an Aducanumab-analogue (Aduhelm^TM; anti-amyloid-β) and a novel anti-Tau antibody, RNF5. We then developed a novel hydrogel-based 2.5D BBB model as a step towards a more physiologically relevant FUS^+MB drug delivery platform. Results: When compared to untreated cells, the delivery of Aducanumab-analogue and RNF5 was significantly increased (up to 1.73 fold), across the Transwell-based BBB models following FUS^+MB treatment. Our results also demonstrated the safety of FUS^+MB indicated by minimal changes in iBEC transcriptome as well as little or no changes in iBEC or iAstrocyte viability and inflammatory responses within the first 24 h post FUS^+MB. Furthermore, we demonstrated successful iBEC barrier formation in our novel 2.5D hydrogel-based BBB model with significantly increased delivery (1.4 fold) of Aducanumab-analogue following FUS^+MB. Conclusion: Our results demonstrate a robust and reproducible approach to utilize patient cells for FUS^+MB-mediated drug delivery screening in vitro. With such a cell platform for FUS^+MB research previously not reported, it has the potential to identify novel FUS^+MB-deliverable drugs as well as screen for cell- and patient-specific effects of FUS^+MB, accelerating the use of FUS^+MB as a therapeutic modality in AD.

Keywords: Aduhelm; Alzheimer's disease; blood-brain barrier; drug delivery; focused ultrasound.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Antibodies, Monoclonal, Humanized* / administration & dosage
Apolipoprotein E3 / metabolism
Apolipoprotein E4 / metabolism
Blood-Brain Barrier*
Brain / physiology
Drug Delivery Systems / methods
Humans
Hydrogels
Microbubbles

Substances

aducanumab
Apolipoprotein E3
Apolipoprotein E4
Hydrogels
Antibodies, Monoclonal, Humanized