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

Content Provider	Springer Nature : BioMed Central
Author	Wasielewska, Joanna M. Chaves, Juliana C. S. Cabral-da-Silva, Mauricio Castro Pecoraro, Martina Viljoen, Stephani J. Nguyen, Tam Hong Bella, Vincenzo La Oikari, Lotta E. Ooi, Lezanne White, Anthony R.
Abstract	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.
Related Links	https://fluidsbarrierscns.biomedcentral.com/counter/pdf/10.1186/s12987-024-00565-1.pdf
Ending Page	20
Page Count	20
Starting Page	1
File Format	HTM / HTML
ISSN	20458118
DOI	10.1186/s12987-024-00565-1
Journal	Fluids and Barriers of the CNS
Issue Number	1
Volume Number	21
Language	English
Publisher	BioMed Central
Publisher Date	2024-08-13
Access Restriction	Open
Subject Keyword	Neurosciences Hematology Neurobiology Amyotrophic lateral sclerosis Blood-brain barrier In vitro model Antibody TDP-43 Drug delivery Focused ultrasound
Content Type	Text
Resource Type	Article
Subject	Neurology Developmental Neuroscience Medicine Cellular and Molecular Neuroscience
Journal Impact Factor	5.9/2023
5-Year Journal Impact Factor	7.5/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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

C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis

Characterization of passive permeability after low intensity focused ultrasound mediated blood–brain barrier disruption in a preclinical model

The new insight into the inflammatory response following focused ultrasound-mediated blood–brain barrier disruption

Investigating receptor-mediated antibody transcytosis using blood–brain barrier organoid arrays

TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis

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

Similar Documents

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

C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis

Characterization of passive permeability after low intensity focused ultrasound mediated blood–brain barrier disruption in a preclinical model

The new insight into the inflammatory response following focused ultrasound-mediated blood–brain barrier disruption

Investigating receptor-mediated antibody transcytosis using blood–brain barrier organoid arrays

TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis

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