Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD

Afroz, Tariq; Chevalier, E.; Audrain, Mickaël; Dumayne, Christopher; Ziehm, Tamar; Moser, Roger; Egesipe, Anne-Laure; Mottier, Lorene; Ratnam, Monisha; Neumann, Manuela; Havas, Daniel; Ollier, Romain; Piorkowska, Kasia; Chauhan, Mohit; Silva, Alberto B.; Thapa, Samjhana; Stöhr, Jan; Bavdek, Andrej; Eligert, Valerie; Adolfsson, Oskar; Nelson, Peter T.; Porta, Sílvia; Lee, Virginia M.‐Y.; Pfeifer, Andrea; Kosco‐Vilbois, Marie H.; Seredenina, Tamara

doi:10.1016/j.nbd.2023.106050

Cited by 20 publications

(18 citation statements)

References 57 publications

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“…With BBB limiting an estimated 99.8 % of peripherally administered large molecule drugs such as therapeutics antibodies (95), we next tested the possibility of enhancing the permeabilisation of ALS BBB to large molecules with FUS +MB . As a proof-of-concept, we trialled the delivery of anti-TDP-43 antibody, considering promising preclinical development of TDP-43 targeted immunotherapies (96)(97)(98)(99) as well as the recent clinical success of therapeutic antibodies in the treatment of other neurodegenerative disorders (100)(101)(102)(103)(104). Although the utilised anti-TDP-43 antibody has not yet proved therapeutically beneficial, we were previously successful in delivering Aducanumab (Aduhelm TM ) and anti-tau therapeutic antibodies with FUS +MB in human Alzheimer's disease in vitro models (37,41); and a recent clinical study demonstrated beneficial effects of Aducanumab combined with FUS +MB in Alzheimer's disease patients, as compared to Aducanumab alone (104).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…Current anti-TDP-43 aggregation approaches focus on targeting the aggregated forms of the protein to block their formation or neutralize their pathogenic properties. [26][27][28] We believe that these approaches alone are unlikely to succeed in the clinic for the following reasons: 1) they only address the toxic function gained by TDP-43 but not potential deleterious effects due to the loss of its normal functions; 2) multiple strains/conformers of TDP-43 aggregates have been reported, and more are likely to emerge in different TDP-43…”

Section: Discussionmentioning

confidence: 99%

Effective Inhibition of TDP‐43 Aggregation by Native State Stabilization

Yang,

Jasiqi,

Zettor

et al. 2023

Angew Chem Int Ed

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Preventing the misfolding or aggregation of transactive response DNA binding protein with 43 kDa (TDP‐43) is the most actively pursued disease‐modifying strategy to treat amyotrophic lateral sclerosis and other neurodegenerative diseases. In this work, we provide proof of concept that native state stabilization of TDP‐43 is a viable and effective strategy for treating TDP‐43 proteinopathies. Firstly, we leveraged the Cryo‐EM structures of TDP‐43 fibrils to design C‐terminal substitutions that disrupt TDP‐43 aggregation. Secondly, we showed that these substitutions (S333D/S342D) stabilize monomeric TDP‐43 without altering its physiological properties. Thirdly, we demonstrated that binding native oligonucleotide ligands stabilized monomeric TDP‐43 and prevented its fibrillization and phase separation in the absence of direct binding to the aggregation‐prone C‐terminal domain. Fourthly, we showed that the monomeric TDP‐43 variant could be induced to aggregate in a controlled manner, which enabled the design and implementation of a high‐throughput screening assay to identify native state stabilizers of TDP‐43. Altogether, our findings demonstrate that different structural domains in TDP‐43 could be exploited and targeted to develop drugs that stabilize the native state of TDP‐43 and provide a platform to discover novel drugs to treat TDP‐43 proteinopathies.

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“…Preclinical (animal model) research aimed at TDP-43 pathology provide hope on the horizon. 76 In the meantime, a current clinical trial targeting LATE (NCT04120766), is based on the finding that polymorphisms in the ATP Binding Cassette Subfamily C Member 9 (ABCC9) gene are associated with risk for LATE + HS. 47,77 This clinical trial uses the drug nicorandil, a modulator of the ABCC9 encoded potassium channel, to target LATE + HS, which was operationally defined as persons aged > 75 years, with evidence of MTL atrophy, and an absence of AD biomarkers.…”

Section: Risk Factors Clinical Management and Clinical Trialsmentioning

confidence: 99%

“…A primary issue in any clinical trial is the selection of a therapeutic target. Preclinical (animal model) research aimed at TDP‐43 pathology provide hope on the horizon 76 . In the meantime, a current clinical trial targeting LATE (NCT04120766), is based on the finding that polymorphisms in the ATP Binding Cassette Subfamily C Member 9 ( ABCC9 ) gene are associated with risk for LATE + HS 47,77 .…”

Section: Risk Factors Clinical Management and Clinical Trialsmentioning

confidence: 99%

When Alzheimer's isLATE: Why Does it Matter?

Nelson

Schneider

Jicha

et al. 2023

Annals of Neurology

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Recent therapeutic advances provide heightened motivation for accurate diagnosis of the underlying biologic causes of dementia. This review focuses on the importance of clinical recognition of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). LATE affects approximately one‐quarter of older adults and produces an amnestic syndrome that is commonly mistaken for Alzheimer's disease (AD). Although AD and LATE often co‐occur in the same patients, these diseases differ in the protein aggregates driving neuropathology (Aβ amyloid/tau vs TDP‐43). This review discusses signs and symptoms, relevant diagnostic testing, and potential treatment implications for LATE that may be helpful for physicians, patients, and families. ANN NEUROL 2023;94:211–222

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Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD

Cited by 20 publications

References 57 publications

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 cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

Effective Inhibition of TDP‐43 Aggregation by Native State Stabilization

When Alzheimer's isLATE: Why Does it Matter?

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