The Experts below are selected from a list of 111 Experts worldwide ranked by ideXlab platform
Illana Gozes - One of the best experts on this subject based on the ideXlab platform.
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nap Davunetide preferential interaction with dynamic 3 repeat tau explains differential protection in selected tauopathies
PLOS ONE, 2019Co-Authors: Yanina Ivashkopachima, Maya Maornof, Illana GozesAbstract:The microtubule (MT) associated protein Tau is instrumental for the regulation of MT assembly and dynamic instability, orchestrating MT-dependent cellular processes. Aberration in Tau post-translational modifications ratio deviation of spliced Tau isoforms 3 or 4 MT binding repeats (3R/4R) have been implicated in neurodegenerative tauopathies. Activity-dependent neuroprotective protein (ADNP) is vital for brain formation and cognitive function. ADNP deficiency in mice causes pathological Tau hyperphosphorylation and aggregation, correlated with impaired cognitive functions. It has been previously shown that the ADNP-derived peptide NAP protects against ADNP deficiency, exhibiting neuroprotection, MT interaction and memory protection. NAP prevents MT degradation by recruitment of Tau and end-binding proteins to MTs and expression of these proteins is required for NAP activity. Clinically, NAP (Davunetide, CP201) exhibited efficacy in prodromal Alzheimer's disease patients (Tau3R/4R tauopathy) but not in progressive supranuclear palsy (increased Tau4R tauopathy). Here, we examined the potential preferential interaction of NAP with 3R vs. 4R Tau, toward personalized treatment of tauopathies. Affinity-chromatography showed that NAP preferentially interacted with Tau3R protein from rat brain extracts and fluorescence recovery after photobleaching assay indicated that NAP induced increased recruitment of human Tau3R to MTs under zinc intoxication, in comparison to Tau4R. Furthermore, we showed that NAP interaction with tubulin (MTs) was inhibited by obstruction of Tau-binding sites on MTs, confirming the requirement of Tau-MT interaction for NAP activity. The preferential interaction of NAP with Tau3R may explain clinical efficacy in mixed vs. Tau4R pathologies, and suggest effectiveness in Tau3R neurodevelopmental disorders.
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The ADNP Derived Peptide, NAP Modulates the Tubulin Pool: Implication for Neurotrophic and Neuroprotective Activities
2016Co-Authors: Yanina Ivashko-pachima, Illana GozesAbstract:Microtubules (MTs), key cytoskeletal elements in living cells, are critical for axonal transport, synaptic transmission, and maintenance of neuronal morphology. NAP (NAPVSIPQ) is a neuroprotective peptide derived from the essential activity-dependent neuroprotective protein (ADNP). In Alzheimer’s disease models, NAP protects against tauopathy and cognitive decline. Here, we show that NAP treatment significantly affected the alpha tubulin tyrosination cycle in the neuronal differentiation model, rat pheochromocytoma (PC12) and in rat cortical astrocytes. The effect on tubulin tyrosination/ detyrosination was coupled to increased MT network area (measured in PC12 cells), which is directly related to neurite outgrowth. Tubulin beta3, a marker for neurite outgrowth/neuronal differentiation significantly increased after NAP treatment. In rat cortical neurons, NAP doubled the area of dynamic MT invasion (Tyr-tubulin) into the neuronal growth cone periphery. NAP was previously shown to protect against zinc-induced MT/neurite destruction and neuronal death, here, in PC12 cells, NAP treatment reversed zinc-decreased tau-tubulin-MT interaction and protected against death. NAP effects on the MT pool, coupled with increased tau engagement on compromised MTs imply an important role in neuronal plasticity, protecting against free tau accumulation leading to tauopathy. With tauopathy representing a major pathological hallmark in Alzheimer’s disease and related disorders, the current findings provide a mechanistic basis for further development. NAP (Davunetide) is in phase 2/3 clinical trial in progressive supranuclear palsy, a disease presenting M
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intranasal nap Davunetide decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing α synuclein
Pharmacology Research & Perspectives, 2014Co-Authors: Bruce H Morimoto, Alistair J Stewart, Iddo Magen, Regina Ostritsky, Franziska Richter, Chunni Zhu, Sheila M Fleming, Vincent Lemesre, Illana GozesAbstract:Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding α-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (Davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human α-synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits.
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Davunetide peptide therapeutic in neurological disorders
Current Medicinal Chemistry, 2014Co-Authors: Iddo Magen, Illana GozesAbstract:This review focuses on the therapeutic effects and mechanisms of action of NAP (Davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in the laboratory of Prof. Illana Gozes. The effects of NAP and its related peptides in models of neurodegenerative diseases and other neurological disorders will be described here in details. Possible mechanisms of NAP actions include anti-inflammatory effect, antioxidant activity, inhibition of protein aggregation and interaction with microtubules. In line with the fact that all of these features are characteristic to most neurological/neurodegenerative disorders, NAP was found to have beneficial effects on the behavioral manifestations associated with these disorders.
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microtubule stabilizing peptides and small molecules protecting axonal transport and brain function focus on Davunetide nap
Neuropeptides, 2013Co-Authors: Iddo Magen, Illana GozesAbstract:This review focuses on the therapeutic effects and mechanisms of action of NAP (Davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (Davunetide) are reviewed paving the path to future developments.
Yanina Ivashkopachima - One of the best experts on this subject based on the ideXlab platform.
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nap Davunetide preferential interaction with dynamic 3 repeat tau explains differential protection in selected tauopathies
PLOS ONE, 2019Co-Authors: Yanina Ivashkopachima, Maya Maornof, Illana GozesAbstract:The microtubule (MT) associated protein Tau is instrumental for the regulation of MT assembly and dynamic instability, orchestrating MT-dependent cellular processes. Aberration in Tau post-translational modifications ratio deviation of spliced Tau isoforms 3 or 4 MT binding repeats (3R/4R) have been implicated in neurodegenerative tauopathies. Activity-dependent neuroprotective protein (ADNP) is vital for brain formation and cognitive function. ADNP deficiency in mice causes pathological Tau hyperphosphorylation and aggregation, correlated with impaired cognitive functions. It has been previously shown that the ADNP-derived peptide NAP protects against ADNP deficiency, exhibiting neuroprotection, MT interaction and memory protection. NAP prevents MT degradation by recruitment of Tau and end-binding proteins to MTs and expression of these proteins is required for NAP activity. Clinically, NAP (Davunetide, CP201) exhibited efficacy in prodromal Alzheimer's disease patients (Tau3R/4R tauopathy) but not in progressive supranuclear palsy (increased Tau4R tauopathy). Here, we examined the potential preferential interaction of NAP with 3R vs. 4R Tau, toward personalized treatment of tauopathies. Affinity-chromatography showed that NAP preferentially interacted with Tau3R protein from rat brain extracts and fluorescence recovery after photobleaching assay indicated that NAP induced increased recruitment of human Tau3R to MTs under zinc intoxication, in comparison to Tau4R. Furthermore, we showed that NAP interaction with tubulin (MTs) was inhibited by obstruction of Tau-binding sites on MTs, confirming the requirement of Tau-MT interaction for NAP activity. The preferential interaction of NAP with Tau3R may explain clinical efficacy in mixed vs. Tau4R pathologies, and suggest effectiveness in Tau3R neurodevelopmental disorders.
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the adnp derived peptide nap modulates the tubulin pool implication for neurotrophic and neuroprotective activities
PLOS ONE, 2012Co-Authors: Yanina Ivashkopachima, Illana GozesAbstract:Microtubules (MTs), key cytoskeletal elements in living cells, are critical for axonal transport, synaptic transmission, and maintenance of neuronal morphology. NAP (NAPVSIPQ) is a neuroprotective peptide derived from the essential activity-dependent neuroprotective protein (ADNP). In Alzheimer’s disease models, NAP protects against tauopathy and cognitive decline. Here, we show that NAP treatment significantly affected the alpha tubulin tyrosination cycle in the neuronal differentiation model, rat pheochromocytoma (PC12) and in rat cortical astrocytes. The effect on tubulin tyrosination/detyrosination was coupled to increased MT network area (measured in PC12 cells), which is directly related to neurite outgrowth. Tubulin beta3, a marker for neurite outgrowth/neuronal differentiation significantly increased after NAP treatment. In rat cortical neurons, NAP doubled the area of dynamic MT invasion (Tyr-tubulin) into the neuronal growth cone periphery. NAP was previously shown to protect against zinc-induced MT/neurite destruction and neuronal death, here, in PC12 cells, NAP treatment reversed zinc-decreased tau-tubulin-MT interaction and protected against death. NAP effects on the MT pool, coupled with increased tau engagement on compromised MTs imply an important role in neuronal plasticity, protecting against free tau accumulation leading to tauopathy. With tauopathy representing a major pathological hallmark in Alzheimer's disease and related disorders, the current findings provide a mechanistic basis for further development. NAP (Davunetide) is in phase 2/3 clinical trial in progressive supranuclear palsy, a disease presenting MT deficiency and tau pathology.
T Q Melo - One of the best experts on this subject based on the ideXlab platform.
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impairment of mitochondria dynamics by human a53t α synuclein and rescue by nap Davunetide in a cell model for parkinson s disease
Experimental Brain Research, 2017Co-Authors: T Q Melo, K C Van Zomeren, M F R Ferrari, Hendrikus Boddeke, J C V M CoprayAbstract:The formation of oligomers and aggregates of overexpressed or mutant α-synuclein play a role in the degeneration of dopaminergic neurons in Parkinson's disease by causing dysfunction of mitochondria, reflected in their disturbed mobility and production of ROS. The mode of action and mechanisms underlying this mitochondrial impairment is still unclear. We have induced stable expression of wild-type, A30P or A53T α-synuclein in neuronally differentiated SH-SY5Y neuroblastoma cells and studied anterograde and retrograde mitochondrial trafficking in this cell model for Parkinson's disease. In contrast to wild-type and A30P, A53T α-synuclein significantly inhibited mitochondrial trafficking, at first retrogradely and in a later stage anterogradely. Accordingly, A53T α-synuclein also caused the highest increase in ROS production in the dysmobilized mitochondria in comparison to wild-type or A30P α-synuclein. Treatment with NAP, the eight amino acid peptide identified as the active component of activity-dependent neuroprotective protein (ADNP), completely annihilated the adverse effects of A53T on mitochondrial dynamics. Our results reveal that A53T α-synuclein (oligomers or aggregates) leads to the inhibition of mitochondrial trafficking, which can be rescued by NAP, suggesting the involvement of microtubule disruption in the pathophysiology of Parkinson's disease.
Adam L Boxer - One of the best experts on this subject based on the ideXlab platform.
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associations between amantadine usage gait and cognition in psp a post hoc analysis of the Davunetide trial
Frontiers in Neurology, 2020Co-Authors: Marian L Dale, Adam L Boxer, Barbara H Brumbach, Amie L HillerAbstract:Introduction: Amantadine anecdotally improves gait in progressive supranuclear palsy (PSP) but definitive data is lacking. We investigated associations between amantadine usage, gait, cognition, and activities of daily living in 310 subjects with PSP using data from the Davunetide trial. Method: We compared baseline demographics, PSP Rating Scale (PSPRS), Repeat Battery for the Assessment of Neuropsychological Status (RBANS), and Schwab and England Activities of Daily Living (SEADL) scores between subjects taking vs. not taking amantadine using chi-square tests for categorical variables and independent sample t-tests for continuous variables. Using the general linear model (GLM), we tested whether group status predicted total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, and SEADL before and after the 52-weeks follow-up. Results: Subjects taking vs. not taking amantadine were similar at baseline, except subjects taking amantadine had a higher Clinical Global Impression (CGI) Score (p = 0.01). However, the CGI change score did not differ between groups at week 52 (p = 0.10). Using GLM models (controlling for covariates), we found that subjects taking vs. not taking amantadine did not significantly predict total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, or SEADL at baseline, week 52, or the change score between baseline and week 52. Discussion: This post-hoc analysis of the Davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes.
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clinical correlates and baseline predictors of progressive brain atrophy in progressive supranuclear palsy results from the al 108 231 Davunetide trial p5 006
Neurology, 2015Co-Authors: Richard M Tsai, Iryna Lobach, Jennifer L Whitwell, Matthew L Senjem, Clifford R Jack, Adam L BoxerAbstract:Objective: To determine if volumetric MRI (vMRI) brain changes can serve as a biomarker for progressive supranuclear palsy disease (PSP) progression, and whether baseline clinical traits predict brain atrophy rates. Background: The AL-108-231 study was a phase 2/3 double-blind, placebo-controlled trial for PSP. It was conducted at 48 centers on three continents and randomized 313 patients to Davunetide (neurotrophic peptide) or placebo for one year with serial MRI scans and clinical data. This study evaluated the clinical correlates of vMRI changes in PSP. Design/Methods: Patients with baseline and week 52 MRI scans, Progressive Supranuclear Palsy Rating Scale (PSPRS) (n=192), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (n=190) and color trails 1, 2 (n = 190, 183) test scores were included for analysis. Brain volumes derived by label propagation in SPM5. Linear regression was used to investigate the relationship between baseline, changes in PSPRS, RBANS, color trails scores and whole brain, ventricular, midbrain and superior cerebellar peduncle (SCP) volume changes. Age, sex, disease duration, H1 haplotype, CoQ10 status, treatment group and total intracranial volume were used as covariates. Results: Change in PSPRS, RBANS and color trails were correlated with brain volume changes (p<0.01). Baseline RBANS memory, language, total scores and color trails scores significantly predicted whole brain, midbrain volume changes respectively (p<0.01). Baseline PSPRS did not predict brain volume changes. The rate of whole brain, midbrain and ventricular volume changes per annum were similar to and confirm previous findings Conclusions: Our data suggest PSP brain volume changes on vMRI capture disease progression and cognitive changes. vMRI changes may serve as a valuable biomarker or outcome to support disease modifying therapeutic efficacy in future PSP clinical trials. Baseline neuropsychological testing may be useful for patient selection for more efficient future clinical trials. Study supported by: Tau Consortium, Allon Pharmaceuticals, NIH Disclosure: Dr. Tsai has nothing to disclose. Dr. Lobach has nothing to disclose. Dr. Whitwell has nothing to disclose. Dr. Senjem has nothing to disclose. Dr. Jack has received personal compensation for activities with Janssen Pharmaceuticals as a consultant. Dr. Jack has received research support from the National Institutes of Health. Dr. Boxer has received personal compensation for activities with Archer Pharmaceuticals, EnVivo Pharmaceuticals, Grifols, and iPerian as a consultant.
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Davunetide in patients with progressive supranuclear palsy a randomised double blind placebo controlled phase 2 3 trial
Lancet Neurology, 2014Co-Authors: Adam L Boxer, Anthony E Lang, Murray Grossman, David S Knopman, Bruce L Miller, Lon S Schneider, Rachelle S Doody, Andrew J Lees, Lawrence I Golbe, David R WilliamsAbstract:Summary Background In preclinical studies, Davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, Davunetide could be a treatment for PSP. We assessed the safety and efficacy of Davunetide in patients with PSP. Methods In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to Davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. Findings 313 participants were randomly assigned to Davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the Davunetide and placebo groups, respectively). There were no differences in the Davunetide and placebo groups in the baseline PSPRS and SEADL. The Davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (−0·20 [−0·20 to −0·17] vs −0·20 [−0·22 to −0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the Davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the Davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [ Interpretation Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Funding Allon Therapeutics.
Michael Gold - One of the best experts on this subject based on the ideXlab platform.
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Davunetide a review of safety and efficacy data with a focus on neurodegenerative diseases
Expert Review of Clinical Pharmacology, 2013Co-Authors: Bruce H Morimoto, Anthony W Fox, Alistair J Stewart, Michael GoldAbstract:Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of Davunetide include neurodegenerative disorders such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of Davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of Davunetide provide strong evidence that Davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of Davunetide, investigating safety and efficacy provide evidence that Davunetide is generally safe and well-tol...
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critical appraisal of the role of Davunetide in the treatment of progressive supranuclear palsy
Neuropsychiatric Disease and Treatment, 2012Co-Authors: Michael Gold, Bruce H Morimoto, Alistair J Stewart, David R Williams, Stefan Lorenzl, Illana GozesAbstract:Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of tau protein aggregates in the basal ganglia, brainstem and cerebral cortex leading to rapid disease progression and death. The neurofibrillary tangles that define the neuropathology of PSP are comprised of aggregated 4R tau and show a well-defined distribution. Classically, PSP is diagnosed by symptoms that include progressive gait disturbance, early falls, vertical ophthalmoparesis, akinetic-rigid features, prominent bulbar dysfunction and fronto-subcortical dementia. There are currently no effective therapies for the treatment of this rapidly degenerating and debilitating disease. Davunetide is a novel neuroprotective peptide that is thought to impact neuronal integrity and cell survival through the stabilization of microtubules. Preclinical activity in models of tauopathy has been translated to clinical studies, demonstrating pharmacologic activity that has supported further development. Davunetide’s efficacy and tolerability are being tested in a placebo-controlled study in PSP patients, making it the most advanced drug candidate in this indication. This review examines the disease characteristics of PSP, the rationale for treating PSP with Davunetide and assesses some of the challenges of clinical trials in this patient population.
