Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial

Boxer, Adam L.; Qureshi, Irfan A.; Ahlijanian, Michael K.; Grundman, Michael; Golbe, Lawrence I.; Litvan, Irene; Honig, Lawrence S.; Tuite, Paul; McFarland, Nikolaus R.; O’Suilleabhain, Padraig; Xie, Tao; Tirucherai, Giridhar; Bechtold, Clifford; Bordelon, Yvette; Geldmacher, David S.; Grossman, Murray; Isaacson, Stuart; Zesiewicz, Theresa; Olsson, Tina M.; Muralidharan, Kumar Kandadi; Graham, Danielle; O’Gorman, John; Haeberlein, Samantha Budd; Dam, Tien

doi:10.1016/s1474-4422(19)30139-5

Cited by 119 publications

(96 citation statements)

References 33 publications

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“…We believe these findings should have a direct effect on the new era of anti-tau clinical trials that aim to recruit patients with early-stage PSP. 30 Our PSP-RS group data are consistent with data from patients with PSP-RS in the davunetide 6 and tideglusib 7 trials with regard to clinical (age at symptom onset and recruitment), genetic, and imaging profiles and the degree of motor and/or functional impairment at study recruitment. In addition, our baseline PSP Rating Scale and SEADL scores for patients with PSP-RS were consistent with those seen in patients with PSP-RS recruited to the 4RT neuroimaging initiative longitudinal cohort.…”

Section: Discussionsupporting

confidence: 83%

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

et al. 2020

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IMPORTANCE Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. OBJECTIVE To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.

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Section: Discussionsupporting

confidence: 83%

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

et al. 2020

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“…As a methodological note, our choice of hsa-miR-186 as a negative control for APP regulation was not coincidental. This miRNA species is known to downregulate BACE1 and its downregulation during aging may increase risk of AD [108,111].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

et al. 2020

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Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid-β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of 55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

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“…Tau analysis is also performed in CSF in clinical trials and may help to show target engagement. For instance, the BIIB092 antibody in a phase 1b clinical trial in PSP is well tolerated, and its complex with tau is found in CSF [18]. In fact, most of the antibodies described in Table 2 are in clinical trials, and their outcome should be published in the months to come.…”

Section: Antibodiesmentioning

confidence: 99%

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

et al. 2019

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The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.

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Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial

Cited by 119 publications

References 33 publications

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

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