Targeting tau: Clinical trials and novel therapeutic approaches.
paper
Cited
Public
- Authors
- VandeVrede, Lawren; Boxer, Adam L; Polydoro, Manuela
- Year
- 2020
- Journal
- Neuroscience letters
- PMID
- 32380145
- DOI
- 10.1016/j.neulet.2020.134919
- PMCID
- PMC9212860
Tauopathies are a group of over 20 clinicopathological neurodegenerative diseases including Alzheimer's disease (AD), the most common type of dementia, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, among others. Tauopathies are defined by neurodegeneration and the presence of tau aggregates in affected brains regions. Interestingly, regional tau aggregation burden correlates with clinical phenotype and predicts cognitive status. Autosomal dominant mutations in the MAPT gene lead to tau deposition and clinical FTD syndromes with cognitive, behavioral, and motor impairment. Polymorphisms in or around the MAPT gene have also been strongly linked to other proteinopathies including synucleinopathies. Taken together these findings suggests that tau plays a critical role in neurodegeneration and proteinopathies, supporting the idea that tau targeted approaches can be disease-modifying and lead to clinically meaningful benefits in slowing or reversing disease progression. Increasingly, human clinical trials are testing this hypothesis. This article reviews tau-targeted therapies tested in clinical trials as well as agents currently in active development based on publicly disclosed information. We describe the therapeutic approaches of these trials based on the potential pathogenic mechanism they target.
Tau-directed approaches currently being tested in clinical trials. In Approach 1β5, toxic tau gain of function is targeted by removal or modulation of toxic tau species. In Approach 1, anti-sense oligonucleotides (ASOs) are directed against mRNA from the MAPT gene, thereby reducing translation and decreasing tau gene expression. In Approach 2, healthy post-translational modification (PTM) pathways are supported by blocking hyperphosphorylation by kinases, inhibiting removal of O-GlcNAc, and preventing tau acetylation. In Approach 3, toxic tau aggregates are prevented from forming and existing tau aggregates are disrupted by autophagy. In Approach 4 and 5, antibodies are used to clear or sequester pathologic tau species, preventing cell to cell transmission. In contrast to the prior approaches, in Approach 6 tau loss of function is addressed by restoring microtubule stabilization.
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In this knowledge base
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| Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases. | 2021 | 34417470 |
External
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