<scp>Open‐Label</scp> Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy

VandeVrede, Lawren; Dale, Marian L.; Fields, Scott; Frank, M; Hare, Emma; Heuer, Hilary W.; Keith, Kellie; Koestler, Mary; Ljubenkov, Peter A.; McDermott, Dana; Ohanesian, Noelle; Richards, Jennifer C.; Rojas, Julio C.; Thijssen, Elisabeth H.; Walsh, Christine M.; Wang, Ping; Wolf, Amy; Quinn, Joseph F.; Tsai, Richard; Boxer, Adam L.

doi:10.1002/mdc3.12940

Cited by 40 publications

(25 citation statements)

References 33 publications

(64 reference statements)

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“…Young plasma (i.e., fresh frozen plasma derived from healthy donors under the age of 30) advanced into clinical trials for Alzheimer's disease and PSP-RS without a definitive mechanism, but with evidence of functional improvement in cognition in mouse models of AD and aging [166][167][168]. In a pilot open-label trial in 5 patients with PSP-RS, young plasma was found to be safe, but no evidence for efficacy was seen on a range of outcomes [142].…”

Section: Cellular Signalingmentioning

confidence: 99%

“…In 4R-tau transgenic mice, treatment with salsalate, a nonsteroidal antiinflammatory agent with inhibitory action on the acetyltransferase p300, decreased tau aggregation and rescued memory deficits, providing support for clinical trials [170]. However, in a small open-label trial in 9 patients with PSP-RS, salsalate (2250 mg daily) was safe and well tolerated, but no effect was seen on a range of outcomes including the PSP Rating Scale after treatment for 6 months [142].…”

Section: Inhibition Of Tau Acetylationmentioning

confidence: 99%

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Four-Repeat Tauopathies: Current Management and Future Treatments

et al. 2020

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Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a wide breadth of clinical syndromes encompassing diverse symptomatology, with the most common syndromes being progressive supranuclear palsy-Richardson's and corticobasal syndrome. Despite the lack of effective disease-modifying therapies, targeted treatment of symptoms can improve quality of life for patients with 4-repeat tauopathies. However, managing these symptoms can be a daunting task, even for those familiar with the diseases, as they span motor, sensory, cognitive, affective, autonomic, and behavioral domains. This review describes current approaches to symptomatic management of common clinical symptoms in 4-repeat tauopathies with a focus on practical patient management, including pharmacologic and nonpharmacologic strategies, and concludes with a discussion of the history and future of disease-modifying therapeutics and clinical trials in this population. Keywords 4R-tauopathy (4R-tau) . progressive supranuclear palsy (PSP) . Richardson's syndrome (PSP-RS) . corticobasal syndrome (CBS) . corticobasal degeneration (CBD) . atypical parkinsonism

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Section: Cellular Signalingmentioning

confidence: 99%

Section: Inhibition Of Tau Acetylationmentioning

confidence: 99%

Four-Repeat Tauopathies: Current Management and Future Treatments

et al. 2020

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“…Other preclinical studies have shown that the dysregulation of both types of enzymes is involved in tau acetylation and neurodegeneration ( 3, 4, 65–68 ). Additionally, several clinical trials are currently investigating the neuroprotective effect of the pharmacological modulation of p300 and SIRT1 ( 69, 70 ). This study supports the translation of p300 and SIRT1 into targets for drug development for the treatment of tauopathies.…”

Section: Discussionmentioning

confidence: 99%

TSC1 loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

Alquézar

et al. 2020

Preprint

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Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), are collectively known as tauopathies. The vast majority of human tauopathies accumulate non-mutant tau rather than mutant forms of the protein, yet cell and animal models for non-mutant tauopathies are lacking. We previously linked a monoallelic mutation in the TSC1 gene to tau accumulation and FTLD. Now, we have identified new variants in TSC1 that predisposed to other tauopathies such as AD and PSP. These new TSC1 risk variants significantly decreased the half-life of TSC1/hamartin in vitro. Cellular and murine models of TSC1 haploinsufficiency (TSC1+/-) accumulated tau protein that exhibited aberrant acetylation on six lysine residues. Tau acetylation hindered its lysosomal degradation via chaperone-mediated autophagy leading to neuronal tau accumulation. Enhanced tau acetylation in TSC1+/- models was achieved through both an increase in p300 acetyltransferase activity and a decrease in SIRT1 deacetylase levels. Pharmacological modulation of either enzyme restored tau levels. Together, these studies substantiate TSC1 as a novel tauopathy risk gene and advance TSC1 haploinsufficiency as a new genetic model for tauopathy. In addition, these results promote acetylated tau as a rational target for diagnostic and therapeutic modalities in multiple tauopathies.

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“…Moreover, these authors found that salsalate prevents hippocampal atrophy and memory impairment (Min et al, 2015 ). An open-label pilot study (phase 1) of salsalate (2,250 mg/day) in 10 PSP patients found that although salsalate was safe and well-tolerated, the drug did not significantly improve cognitive performance in patients (VandeVrede et al, 2020b ). This may be explained by either the poor penetration of salsalate into the brain (<3%), or by an increase in tau aggregation following reduced tau acetylation.…”

Section: Tau-targeted Therapiesmentioning

confidence: 99%

New Insights Into Drug Discovery Targeting Tau Protein

Soeda

Takashima

2020

Front. Mol. Neurosci.

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Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

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Open‐Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy

Cited by 40 publications

References 33 publications

Four-Repeat Tauopathies: Current Management and Future Treatments

Four-Repeat Tauopathies: Current Management and Future Treatments

TSC1 loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

New Insights Into Drug Discovery Targeting Tau Protein

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