A multicellular brain spheroid model for studying the mechanisms and bioeffects of ultrasound-enhanced drug penetration beyond the blood‒brain barrier

Paranjape, Anurag N.; D’Aiuto, Leonardo; Zheng, Wenxiao; Chen, Xucai; Villanueva, Flordeliza S.

doi:10.1038/s41598-023-50203-3

Cited by 3 publications

(1 citation statement)

References 59 publications

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“…To this end, there are many ongoing investigations exploring this concept in both cardiac and oncology contexts. 44 , 53 , 116 Indeed, comparisons of gene quantification using this natively intravenous approach vs. direct intramyocardial injection has not been thoroughly addressed but would be a useful measure to appreciate the efficiency of ultrasound-assisted cardiac gene delivery. Further elucidation of this concept will drive modulation of the approach itself (e.g., pulse parameters, microbubble concentration) toward improving the delivery efficiency.…”

Section: Outlook and Future Directionsmentioning

confidence: 99%

Cardiac gene delivery using ultrasound: State of the field

Singh,

Memari,

et al. 2024

Molecular Therapy - Methods & Clinical Development

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Section: Outlook and Future Directionsmentioning

confidence: 99%

Cardiac gene delivery using ultrasound: State of the field

Singh,

Memari,

et al. 2024

Molecular Therapy - Methods & Clinical Development

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A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

Wasielewska,

Castro Cabral-da-Silva,

Pecoraro

et al. 2024

Preprint

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BackgroundAmyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS+MB) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS+MB-mediated drug delivery across ALS patients’ BBB has not yet been reported. Similarly, the effects of FUS+MBon human ALS BBB cells remain unexplored.MethodsHere we established the first FUS+MB-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS+MBbioeffectsin vitro.ResultsGenerated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including changes to BBB integrity, permeability and TDP-43 proteinopathy. Our results also identified differences between sporadic ALS and familial (C9orf72expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer openingin vitrowith a lack of adverse cellular effects of FUS+MB. This was accompanied by the molecular bioeffects of FUS+MBin ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS+MBin C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS+MBcan be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALSin vitromodel.ConclusionsTogether, our study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS+MBand provides a fully-human platform for FUS+MB-mediated drug delivery screening on an ALS BBBin vitromodel.

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A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery

Wasielewska,

Chaves,

Cabral-da-Silva

et al. 2024

Fluids Barriers CNS

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Background Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS + MB ) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS + MB -mediated drug delivery across ALS patients’ BBB has not yet been reported. Similarly, the effects of FUS + MB on human ALS BBB cells remain unexplored. Methods Here we established the first FUS + MB -compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS + MB bioeffects in vitro. Results Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial ( C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS + MB as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS + MB treated cells. This was accompanied by the molecular bioeffects of FUS + MB in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS + MB in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS + MB can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model. Conclusions Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS + MB and provides a fully-human platform for FUS + MB -mediated drug delivery screening on an ALS BBB in vitro model. Supplementary Information The online version contains supplementary material available at 10.1186/s12987-024-00565-1.

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A multicellular brain spheroid model for studying the mechanisms and bioeffects of ultrasound-enhanced drug penetration beyond the blood‒brain barrier

Cited by 3 publications

References 59 publications

Cardiac gene delivery using ultrasound: State of the field

Cardiac gene delivery using ultrasound: State of the field

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery

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