Passive Immunotherapy for Tau Pathology

Davies, Peter

doi:10.1016/b978-0-12-802173-6.00014-9

Cited by 2 publications

(4 citation statements)

References 106 publications

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“…Small molecule drugs have advantages over immunotherapeutic approaches targeting tau [2,[40][41][42][43][44]. In brief, orally available small molecules can be designed to penetrate the bloodbrain barrier, to enter cells where tau is aggregating, and to access extracellular vesicles that may be vectors of tau seeds that spread tau pathology [45].…”

Section: Discussionmentioning

confidence: 99%

“…Long-term treatment for chronic diseases such as AD requires therapies that are safe, effective, and economically feasible-especially for early preventive treatment strategies. The amyloid cascade hypothesis has been the dominant paradigm for drug discovery for AD, but recent advances in the understanding of tau biology in neurodegenerative diseases and difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for drug discovery [2][3][4][5][6][7], particularly tau oligomers [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice

Davidowitz,

Lopez,

Jimenez

et al. 2023

PLoS ONE

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Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice

Davidowitz,

Lopez,

Jimenez

et al. 2023

PLoS ONE

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“…Most programs targeting tau are using an immunotherapeutic approach [3,[76][77][78][79][80]. However, there are multiple advantages of using small molecule therapeutics to target the accumulation of tau pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Orally available, small molecules can be designed to penetrate the blood-brain-barrier, to enter cells where tau is aggregating, and to access extracellular vesicles that may be vectors of tau seeds causing spread of tau pathology, whereas, only 0.1-0.2% of intravenous-administered antibody levels can access the cerebrospinal fluid. An active immunotherapeutic approach may trigger a harmful autoimmune response [76]. The phenomenon of epitope spreading can occur that creates an immune response to other epitopes in the same or similar proteins that precludes limiting the immune response to a single determinant [81].…”

Section: Discussionmentioning

confidence: 99%

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Davidowitz

Krishnamurthy

Lopez

et al. 2020

JAD

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Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

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Passive Immunotherapy for Tau Pathology

Cited by 2 publications

References 106 publications

Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice

Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

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