Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome

Tsai, Richard; Miller, Zachary A.; Koestler, Mary; Rojas, Julio C.; Ljubenkov, Peter A.; Rosen, Howard J.; Rabinovici, Gil D.; Fagan, Anne M.; Cobigo, Yann; Brown, Jesse A.; Jung, June‐Ho; Hare, Emma; Geldmacher, David S.; Natelson-Love, Marissa; McKinley, Emily C.; Luong, Phi; Chuu, Emmeline L.; Powers, Ryan; Mumford, Paige; Wolf, Amy; Wang, Ping; Shamloo, Merhdad; Miller, Bruce L.; Roberson, Erik D.; Boxer, Adam L.

doi:10.1001/jamaneurol.2019.3812

Cited by 97 publications

(80 citation statements)

References 33 publications

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“…For example, TPI‐287/abeotaxane is a brain‐penetrant microtubule stabilizer that indicated efficacy in PS19 tau transgenic mice. Recent basket clinical trials on different tauopathies to test the safety, tolerability, and potential efficacy of TPI‐287 infusion indicated that (i) TPI‐287 was generally well tolerated, although anaphylactoid reactions occurred in 3/26 of AD patients, but not in 42 4‐repeat tauopathies (4RT) patients, which led to a discussion of a potential difference in sensitivity profiles of AD and 4RT patients; (ii) CSF YKL‐40 level changed in TPI‐287 groups; and (iii) the AD treatment group showed a smaller decline in MMSE scores than did the placebo group, although the difference was not significant (Tsai et al, ). Still, antimitotics remain candidate drugs for AD management.…”

Section: Effects Of Cell Cycle Interfering Drugs On Ad Modelsmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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Section: Effects Of Cell Cycle Interfering Drugs On Ad Modelsmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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“…Currently, a variety of experimental therapeutic approaches to PSP have been proposed, mainly focused on tau protein as a target, but relatively few late-phase clinical trials have been conducted. 1,[4][5][6][7][8] Large, international clinical trials and multicenter, longitudinal, observation studies have revealed striking consistency in rates of change of clinical rating scales of PSP symptomatology, 9 particularly on the Progressive Supranuclear Palsy Rating Scale (PSPRS) and Schwab and England Activity of Daily Living scale (SEADL), 10 the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), 11 volumetric MRI measures of midbrain atrophy, 12 and cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentrations. 13 This suggests that natural history data from earlier longitudinal studies could be used to gauge the potential promise of novel therapeutic interventions, before the initiation of larger, placebo-controlled trials or in situations where such trials are not practical or possible, including commonly used therapeutics, lifestyle interventions that are widely available, or other desired off-label interventions by patients and families.…”

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confidence: 99%

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

VandeVrede

Dale

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et al. 2020

Movement Disord Clin Pract

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Background Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off‐label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence‐based knowledge to guide future treatment decisions. Objectives To describe an open‐label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP‐Richardson's syndrome (PSP‐RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. Methods For 6 months, 10 PSP‐RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP‐RS patients from the davunetide clinical trial and the 4‐Repeat Tauopathy Neuroimaging Initiative. Results Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (–0.07 ± 0.03), young plasma (–0.06 ± 0.03), and historical controls (–0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. Conclusions Neither salsalate nor young plasma had a detectable effect on disease progression in PSP‐RS. Focused open‐label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP‐directed therapies.

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“…This avenue was explored by using drugs that stabilize microtubules. Promising results were obtained in tau mouse models but no beneficial effect was observed in humans ( 171 – 173 ). This could be explained by the fact that a recent study reported that tau does not stabilize microtubules but exerts the opposite effect ( Figure 3 ).…”

Section: Section (Iv) Hyperphosphorylated Tau: Direct or Indirect Thementioning

confidence: 99%

Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology

et al. 2021

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Tau protein, a neuronal microtubule-associated protein, becomes hyperphosphorylated in several neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau is correlated to its redistribution from the axon to the somato-dendritic compartment at early stages of tauopathies. Interestingly, tau hyperphosphorylation begins in different regions of the brain in each tauopathy. In some regions, both neurons and glial cells develop tau hyperphosphorylation. Tau hyperphosphorylation is also observed in physiological conditions such as hibernation and brain development. In the first section of present article, we will review the spatiotemporal and cellular distribution of hyperphosphorylated tau in the most frequent tauopathies. In the second section, we will compare the pattern of tau hyperphosphorylation in physiological and pathological conditions and discuss the sites that could play a pivotal role in the conversion of non-toxic to toxic forms of hyperphosphorylated tau. Furthermore, we will discuss the role of hyperphosphorylated tau in physiological and pathological conditions and the fact that tau hyperphosphorylation is reversible in physiological conditions but not in a pathological ones. In the third section, we will speculate how the differences and similarities between hyperphosphorylated tau in physiological and pathological conditions could impact the elaboration of therapies to prevent tau pathology. In the fourth section, the different therapeutic approaches using tau as a direct or indirect therapeutic target will be presented.

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Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome

Cited by 97 publications

References 33 publications

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

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

Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology

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