Drug Development.

Background: Tau proteins aggregate in a number of neurodegenerative disorders known as tauopathies. Various studies have highlighted the role of microtubule-binding domains in the intracellular aggregation of Tau protein.

Method: Using a library of synthetic VHHs humanized in collaboration with Hybrigenics, we have developed a number of anti-tau VHHs.

Drug Development.

Background: Only about 50% of the variance in cognitive decline occurring during Alzheimer's pathogenesis is attributable to standard AD biomarkers (cerebrocortical Aβ, pathological tau, and atrophy) (Tosun et al., Alzheimer's Dement. 18: 1370, 2022).

Drug Development.

Background: Phase 3 randomized clinical trials within Alzheimer's Disease (AD) typically last over 18 months. Post-baseline participants can use additional treatment for Alzheimer's disease, potentially impacting the cognitive ability as evaluated by the primary endpoint. Consequently, this could overestimate or underestimate the treatment effect, depending on the distribution of usage between treatment arms.

Drug Development.

Background: To improve clinical translatability of non-clinical in-vivo Alzheimer's disease (AD) models, a humanized APP knock-in mouse model (APP) was recently created (Xia, D. et al., 2022).

Drug Development.

Background: Seizures in Alzheimer's Disease (AD) are increasingly recognized to occur and can increase cognitive decline and reduce survival compared to unaffected age-matched peers (Lyou et al. 2018). Administration of antiseizure medicines (ASMs) to AD patients with epileptiform activity may improve cognition (Vossel et al.

Drug Development.

Background: Clinical outcome assessments (COAs) that measure functional capacities are key tools to evaluate efficacy in Alzheimer's disease (AD) clinical trials. The Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale is frequently used to assess changes in both basic and instrumental activities of daily living, but there is no clear consensus on what magnitude of change on this scale may be considered clinically meaningful. To address this question, we conducted anchor-based analyses (as recommended by the FDA) to explore meaningful within-patient/participant change thresholds on the ADCS-ADL.

Drug Development.

Background: Genetic studies have established that loss of function SORL1 gene variants are associated with Alzheimer's disease (AD). SORL1 encodes an endosomal trafficking receptor, SORLA, which regulates endosomal protein recycling through its interaction with the retromer core complex (consisting of VPS26, VPS35 and VPS29). Deficits in the levels and function of the SORLA-retromer complex are thought to underlie AD.

Drug Development.

It is well recognised that Alzheimer's disease and related dementia disorders (ADRD) are associated with very high societal costs. The total global costs of dementia have been estimated to over 1.3 trillion US$ annually (Wimo, Seeher et al.

Drug Development.

Background: Microbiota of the distal part of the intestine produces Urolithin A (Uro A) as a derivative of ellagitannins hydrolysis. Recently, the mitophagy, anti-inflammatory, and antioxidant properties of Uro A have focused more attention on its probable beneficial effects on neurodegenerative states. The purpose of this research was to study the impact of Uro A on the histopathology of the cerebellum in a rat model of streptozotocin-induced Alzheimer's disease.

Drug Development.

Background: Gamma desynchronization is an early pathophysiological event in Alzheimer's disease with a disturbance in oscillation in the gamma frequency range 30-80 Hz. This disruption was found to be directly related to the disease progression and severity. Thus, the use of transcranial alternating current stimulation (tACS) possessed greater interest.

Correction: Camptothecin-based prodrug nanomedicines for cancer therapy.

Correction for 'Camptothecin-based prodrug nanomedicines for cancer therapy' by Renshuai Zhang , , 2023, , 17658-17697, https://doi.org/10.1039/D3NR04147F.

Drug Development.

Background: The Mini-Mental State Examination (MMSE) is a common screening tool in Alzheimer's disease (AD) clinical trials. MMSE score inflation at inclusionary visits poses challenges by potentially amplifying placebo responses and complicating the detection of treatment effects. Despite these concerns, prior research (e.

Drug Development.

Background: Randomized placebo-controlled trials (RCTs) are the gold standard to evaluate efficacy of new drug treatments for Alzheimer's disease. For example, the United States FDA approved the brain amyloid-targeting drug lecanemab following CLARITY AD, Biogen and Eisai's Phase 3 RCT. However, recruiting enough participants for a high-powered and demographically representative trial is difficult and expensive.

Drug Development.

Background: Early-onset Alzheimer's disease (EOAD) associated with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants increases risk of seizures. Targeting epileptiform activity with antiseizure medicine (ASM) administration to AD patients may beneficially attenuate cognitive decline (Vossel et al, JAMA Neurology 2021). However, whether mechanistically distinct ASMs differentially suppress seizures in discrete EOAD models is understudied (Lehmann et al, Neurochem Res 2021).

Drug Development.

Background: Solanezumab, a promising treatment for Alzheimer's disease, has captured the attention of the medical community. This monoclonal antibody is designed to target and clear beta-amyloid plaques, a hallmark feature of Alzheimer's, from the brain. While initial clinical trials showed mixed results, ongoing research is exploring its potential to slow cognitive decline and improve the lives of those affected by this devastating neurodegenerative condition.

Drug Development.

Background: TAR-DNA-binding protein 43 (TDP43), is a pathologic marker in neurodegenerative diseases including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. The aggregation of TDP-43, a crucial RNA-binding protein, is a consequence of post-translational modifications (PTMs) that disrupt its normal function. PTMs such as phosphorylation and ubiquitination contribute to the aberrant accumulation of TDP-43 aggregates, leading to neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

Drug Development.

Background: Progranulin (PGRN), a glycoprotein secreted by microglia and neurons, regulates lysosomal function, neuroinflammation, and has neurotrophic effects. Variants in the granulin gene (GRN) that cause a reduction of PGRN in plasma and cerebrospinal fluid (CSF) are associated with an increased risk of Alzheimer's disease (AD). The sortilin receptor (SORT1) on neurons and microglia regulates PGRN degradation.

Drug Development.

Background: The increased incidence of Alzheimer's disease (AD) rate represent an unmet medical need and thus critical for the development of novel molecular therapeutics. Recent work focusing on patients with apoE4 alleles has highlighted the association of brain cholesterol dysregulation with elevated pathological burden and neurodegeneration. These studies have highlighted the importance of the nuclear receptor Liver X receptor (LXR) for developing AD therapies.

Drug Development.

Background: In a 16-week, 91-patient placebo-controlled clinical study in DLB ("AscenD-LB";NCT04001517), neflamapimod improved outcomes on the CDR Sum-of-Boxes (p = 0.023 vs. placebo) and Timed Up and Go test (p = 0.

Drug Development.

Background: Neurological disorders are at epidemic levels in the world today. Various proteins are being targeted for the development of novel molecular therapeutics; however, no small-molecule inhibitors have been discovered. Recent studies suggest that there are few molecules in clinical trials for various secretase (α, β, and γ), caspase, and calpain inhibitors.

Drug Development.

Background: Major contributors to AD pathogenesis include aggregates of amyloid-β (Aβ) peptides, hyperphosphorylated tau protein, and neuroinflammation. No currently approved treatment stops or significantly slows the progression of AD. Nevertheless, one class of agents that has shown promise is metal chelators.

Drug Development.

Background: Alzheimer's disease (AD) is characterized by hallmark amyloid plaques and neurofibrillary tangles as well as by a significant loss of myelin in the cerebral cortex and other brain regions, which contributes to neurodegeneration and cognitive decline. Remyelination, of the myelin sheath by oligodendrocytes, is a process that may be impaired in neurodegenerative diseases. Depending on the severity of the disease, there occurs loss or partial damage of the myelin sheath surrounding the neuron leading to memory deficits.

Drug Development.

Background: OLX-07010 is an oral small molecule inhibitor of tau self-association that prevented the accumulation of tau aggregates in the htau mouse model expressing wild type human CNS tau isoforms and in P301L tau JNPL3 mice using chronic treatment by administration in diet (Davidowitz et al., 2020, PMID: 31771053; 2023 PMID:37556474). A therapeutic study of JNPL3 mice with chronic treatment from 7-12 months of age inhibited the progression of tau aggregation and improved motor coordination.

Drug Development.

Background: The prohibitive costs of drug development for Alzheimer's Disease (AD) emphasize the need for alternative in silico drug repositioning strategies. Graph learning algorithms, capable of learning intrinsic features from complex network structures, can leverage existing databases of biological interactions to improve predictions in drug efficacy. We developed a novel machine learning framework, the PreSiBOGNN, that integrates muti-modal information to predict cognitive improvement at the subject level for precision medicine in AD.

Drug Development.

Amyloid β (Aβ) has been confirmed as a therapeutic target in AD by recent findings in Phase 3 trials with anti-Aβ antibodies. Modulators of γ-secretase (GSMs) are an emerging complementary approach to target amyloid. GSMs "modulate" the interaction between γ-secretase and amyloid precursor protein (APP), leading to a reduced production of long, amyloidogenic Aβ42 and Aβ40 and to concomitantly increased levels of the shorter, non amyloidogenic Aβ37 and Aβ38.