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Bayesian Frameworks for Rare Disease Clinical Development Programs
Published in Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger, Bayesian Methods in Pharmaceutical Research, 2020
Freda Cooner, Forrest Williamson, Bradley P. Carlin
Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by the accumulation of aggregates of tau protein in the brain (Rossi, 2018). Several disease-modifying agents have been studied for the treatment of PSP. We consider two randomized, placebo controlled trials of putative disease-modifying agents in PSP. The first trial is a Phase II/III double-blind, parallel group trial of davunetide (30mg) versus placebo (Boxer and et al., 2014). The second trial is a Phase II, double-blind, parallel group trial of two doses of tideglusib (600 and 800mg) versus placebo (Tolosa and et al., 2014). Neither study met its 52-week primary outcome, but these trials have generated valuable data for our understanding of placebo response in PSP.
Focusing on oligomeric tau as a therapeutic target in Alzheimer’s disease and other tauopathies
Published in Expert Opinion on Therapeutic Targets, 2023
Tau is a substrate for multiple types of PTMs, which includes phosphorylation, acetylation, glycosylation, methylation, and ubiquitination [8,11]. Of the many tau PTMs, phosphorylation is the most extensively characterized. Tau kinases include cyclin-dependent kinase 5 (cdk5), cyclic AMP-dependent protein kinase A (PKA), calmodulin-dependent protein kinase II (CaMKII), glycogen synthase kinase-3β (GSK-3β), and sarcoma/Abelson (Src/Abl) family kinases [8,37]. Of these, GSK-3β serves as a prototypical example, and was the target of the first kinase inhibitors tested in clinical trials for tauopathies [49]. GSK-3β was identified as a potential therapeutic target based on the premise that GSK-3β inhibition should reduce tau hyperphosphorylation and therefore tau aggregation. However, clinical trials for Tideglusib, a potent GSK-3β inhibitor, did not demonstrate efficacy in mild-to-moderate AD (NCT01350362) or PSP (NCT01049399) [17,18].
Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2016–2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Carlos Roca, Nuria E. Campillo
GSK-3 is still a key target in a great amount of diseases. In this sense, the search of patents during the period of 2016–2019 has allowed to identify different new therapeutic uses. Cyclin-dependent kinase-like 5 (CDKL5) disorder is a neurodevelopment disease characterized by epileptic seizures, development delay and intellectual disability. Fuchs et al. showed an increased activity of GSK-3β, using a Cdkl5 knockout (KO) mouse model together with the associated defects of the disorder [52]. Treatment with Tideglusib (Figure 1) during the juvenile period improved hippocampal development and hippocampus-dependent behaviors in Cdkl5 KO mice. Ciani et al. from Alma Mater Studiorum of U. di Bologna claims the use of Tideglusib as treatment of CDKL5 disorders [53].
Drug development for Alzheimer’s disease: review
Published in Journal of Drug Targeting, 2019
Kejing Lao, Naichun Ji, Xiaohua Zhang, Wenwei Qiao, Zhishu Tang, Xingchun Gou
Tau phosphorylation seems to represents one of the most critical pathogenic stages of tauopathy; therefore, kinases and phosphatases involved in tau hyperphosphorylation and dephosphorylation, respectively, represent excellent enzymatic targets for anti-tau therapy. Phosphorylation of tau is controlled through different kinases and phosphatases. Among them, the glycogen synthase kinase 3β (GSK-3β) is a key target that regulates tau phosphorylation, which is also involved in amyloid processing and gene transcription [68]. Several GSK-3β inhibitors are under development. Tideglusib (NP-031112, NP-12, 15) is the only GSK-3β inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. It reduces tau phosphorylation and prevents apoptotic death in human neuroblastoma cells and 66 murine primary neurons [69]. However, a short-term (26-week) phase II trial in 306 patients with AD was acceptably safe and delayed the loss of brain volume, but produced no clinical benefit [70].