Opportunities and challenges in delivering biologics for Alzheimer’s disease by low-intensity ultrasound

Chen, Liyu; Cruz, Esteban; Oikari, Lotta E.; Padmanabhan, Pranesh; Song, Jae Hee; Götz, Jürgen

doi:10.1016/j.addr.2022.114517

Cited by 19 publications

(23 citation statements)

References 212 publications

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“…A major hindrance in treating neurodegenerative diseases such as AD is the low bioavailability of therapeutics in the brain due to the BBB, which inhibits the entry of most large molecule drugs, including antibodies. The FUS +MB technique is a relatively novel technology that allows the transient opening of the BBB to achieve efficient drug delivery into the CNS 63 . A small number of clinical studies using FUS +MB in AD patients have demonstrated the safety of this technique 21 , 23 - 25 , making it a promising tool for increased drug delivery.…”

Section: Discussionmentioning

confidence: 99%

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

Wasielewska¹,

Chaves²,

Johnston³

et al. 2022

Theranostics

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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.

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Section: Discussionmentioning

confidence: 99%

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

Wasielewska¹,

Chaves²,

Johnston³

et al. 2022

Theranostics

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“…51 The safety and noninvasiveness of US, which has been widely used to trigger "on-demand" drug delivery remotely with deep tissue penetration, has been recognized. 52 However, poor spatial resolution of US imaging hinders the precise biomedical applications. Through the combination of NIR-II PA imaging and US-controlled active propelling characteristics, our group designed a nanomotor-based Janus nanoprobe for active NIR-II PA imaging guided cancer therapy.…”

Section: ■ Exogenous Stimuli-responsive Imagingmentioning

confidence: 99%

“…US has been widely used in clinics to image internal tissues for further disease diagnosis and treatment . The safety and noninvasiveness of US, which has been widely used to trigger “on-demand” drug delivery remotely with deep tissue penetration, has been recognized . However, poor spatial resolution of US imaging hinders the precise biomedical applications.…”

Section: Exogenous Stimuli-responsive Imagingmentioning

confidence: 99%

Optical and Photoacoustic Imaging In Vivo: Opportunities and Challenges

Zhang

Chen

et al. 2023

Chemical & Biomedical Imaging

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Optical and photoacoustic imaging plays an important role in biomedical applications owing to its noninvasiveness and high resolution. Fluorescence imaging and photoacoustic imaging emerge as powerful tools to deconstruct molecular information and investigate biological processes in vivo. Despite great progress has been achieved in chemical probe synthesis, how to design probes with optimal fluorescence or photoacoustic imaging performance to dynamically visualize the biological process in vivo still faces challenges. From this perspective, we will focus on the advanced development of fluorescence and photoacoustic imaging in vivo. Furthermore, concerns and prospects for future imaging in vivo will be demonstrated.

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“…Recently, it has been shown that low-intensity focused ultrasound (LIFU) combined with intravenously circulating microbubbles can be applied safely to transiently open the BBB (8)(9)(10)(11)(12)(13)(14). This would allow drug delivery (15,16) in human patients and successfully enhance intracerebral viral vector delivery in AD, HD, and PD rodent models (17,18). Efficient BBB opening in nonhuman primates (NHPs) has been achieved previously (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

“…This allows visualization of a possible scenario where treatments acting on the dopaminergic nigrostriatal system could be administered very early in disease evolution (32). Accordingly, we have also used 18 F-Choline positron emission tomography (PET) imaging to demonstrate that the same BBB opening methodology is functionally successful in the putamen and midbrain structures of patients with PD. Together, our results constitute a valuable step toward achieving the goal of providing putative therapies for PD and other neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

et al. 2023

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Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson’s disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson’s disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18 F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders.

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Opportunities and challenges in delivering biologics for Alzheimer’s disease by low-intensity ultrasound

Cited by 19 publications

References 212 publications

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

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

Optical and Photoacoustic Imaging In Vivo: Opportunities and Challenges

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

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