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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| 20 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β Kinase inhibitors | Valproate (Depakote, divalproex, valproic acid), another small molecule FDA-approved mood stabilizerβ¦ |
| 21 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β Kinase inhibitors | Tideglusib (NP031112, Nypta, Zentylor, NP12) was a novel small molecule specifically designed as aβ¦ |
| 22 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β Kinase inhibitors | Fyn, another kinase implicated in post-translational modification of tau, belongs to the Src familyβ¦ |
| 23 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β Kinase inhibitors | The most recent kinase being tested in clinical trials is Nilotinib (Tysigna, AMN107), a smallβ¦ |
| 24 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β O-GlcNAcase inhibitors | Supporting the hypothesis that targeting O-GlcNAcylation can decrease tau hyperphosphorylation, anβ¦ |
| 25 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β O-GlcNAcase inhibitors | Another OGA inhibitor, ASN120290 (ASN-561), has been developed by Asceneuron, with preclinical dataβ¦ |
| 26 | Therapeutic approaches to toxic tau gain of function β Approach 2: modulate tau post-translational modification (PTM) β Acetylation inhibitors | As described above, abnormal acetylation at lysine residues can prevent physiologic clearance ofβ¦ |
| 27 | Therapeutic approaches to toxic tau gain of function β Approach 3: disrupt tau aggregation | While natively unfolded, the MTBR tandem repeat region (3R/4R) can undergo tau-tau binding resultingβ¦ |
| 28 | Therapeutic approaches to toxic tau gain of function β Approach 3: disrupt tau aggregation β Tau aggregation inhibitors | Based on the preclinical data, methylene blue was rebranded as Rember by TauRx Therapeutics, andβ¦ |
| 29 | Therapeutic approaches to toxic tau gain of function β Approach 3: disrupt tau aggregation β Tau aggregation inhibitors | Unfortunately, in two companion Phase 3 trials involving nearly 1700 patients with mildβ¦ |
| 30 | Therapeutic approaches to toxic tau gain of function β Approaches 4 and 5: blocking cell-to-Cell tau transmission | Tau is mainly an intracellular protein, however in recent years there is growing evidence that tauβ¦ |
| 31 | Therapeutic approaches to toxic tau gain of function β Approaches 4 and 5: blocking cell-to-Cell tau transmission | The concept of tau spreading created an opportunity for novel therapeutic strategies targetingβ¦ |
| 32 | Therapeutic approaches to toxic tau gain of function β Approach 4: active immune clearance of tau | Harnessing the immune system to clear protein aggregates was one of the earliest and most excitingβ¦ |
| 33 | Therapeutic approaches to toxic tau gain of function β Approach 4: active immune clearance of tau | However, one past trial targeting amyloid with active immunotherapy (AN1792), caused aβ¦ |
| 34 | Therapeutic approaches to toxic tau gain of function β Approach 4: active immune clearance of tau β Vaccinations | The first tau-directed vaccine tested in clinical trials was AADvac1, developed by Axon Neuroscienceβ¦ |
| 35 | Therapeutic approaches to toxic tau gain of function β Approach 4: active immune clearance of tau β Vaccinations | A Phase 1 first-in-human trial of AADvac1 in 30 patients with mild to moderate AD showed excellentβ¦ |
| 36 | Therapeutic approaches to toxic tau gain of function β Approach 4: active immune clearance of tau β Vaccinations | ACI-35, an alternative vaccination agent, was initially developed by AC Immune and later licensed byβ¦ |
| 37 | Therapeutic approaches to toxic tau gain of function β Approach 5: passive immune clearance of tau | Passive immune clearance is the largest area of active intervention and excitement in the field,β¦ |
| 38 | Therapeutic approaches to toxic tau gain of function β Approach 5: passive immune clearance of tau | Current tau monoclonal antibody targets include N-terminal, mid-domain regions, and specificβ¦ |
| 39 | Therapeutic approaches to toxic tau gain of function β Approach 5: passive immune clearance of tau β Monoclonal antibodies | One of the first completed trials using a passive antibody approach for tau clearance was a Phase 1β¦ |
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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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