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Novel regulation of autophagic flux for the treatment of Alzheimer's disease

自噬流的新调节用于治疗阿尔茨海默氏病

基本信息

批准号：
10381804
负责人：
William J Greenlee
金额：
$ 49.93万
依托单位：
CERACUITY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381804
关键词：
Affect Age Aging Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Autophagocytosis Autophagosome Behavior Behavioral Biological Assay Brain Cell Count Cell model Cells Characteristics Chemicals Chemistry Chronic Clinical Collection Data Data Set Dementia Development Disease Disease Progression Dose Enzymes Excision FDA approved Failure Future Goals Health Healthcare Human Image Impaired cognition Impairment In Vitro Laboratories Lead Libraries Lysosomes Modeling Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oral Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Phase Phenotype Population Process Property Proteins Regulation Reproducibility Research Rivers Rodent Model Running Series Signal Transduction Slice Source Structure-Activity Relationship Tauopathies Testing Therapeutic Vacuole Validation Zebrafish base blood-brain barrier penetration clinical efficacy cost counterscreen effective therapy high throughput screening hyperphosphorylated tau improved in vivo inhibitor lead candidate lead series liquid chromatography mass spectrometry mutant neuron loss novel phospholipase D1 phosphoric diester hydrolase pre-clinical prevent protein aggregation proteotoxicity response screening small molecule socioeconomics success tau Proteins tau aggregation tau mutation tau-1 therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY Alzheimer’s Disease (AD) is a progressive neurodegenerative disease that leads to cognitive decline. According to the WHO (2020), AD affects 30 million people worldwide. This number is expected to triple by 2050, with an annual forecasted global cost of over $600 billion. Currently, no disease-modifying treatments are available and no new AD therapeutics have been approved by the FDA in over 15 years. AD is characterized in part by the accumulation of phosphorylated tau proteins. Despite promising preclinical data, therapeutics targeting tau accumulation have not shown clinical efficacy. Autophagy is a multistep process that facilitates the removal of aggregated proteins and is essential to prevent neurodegeneration. This clearance of proteins is termed autophagic flux. AD is characterized by aberrant accumulation of endogenous proteins, specifically tau accumulation into intracellular neurofibrillary tangles. AD brains show neuronal accumulation of autophagic vacuoles indicating that while autophagosomes form and envelop proteinopathies, they are not efficiently cleared. The autophagic flux pathway becomes less efficient with aging and disease stage whereby, autophagosome maturation and autolysosome clearance are critically impaired. In neurodegenerative diseases, this can result in the retention of proteotoxic substrates like hyperphosphorylated and aggregated tau. These observations support the targeting of dysfunctional autophagic flux as a therapeutic approach for AD. PLD1 is an inducible, lipolytic phosphodiesterase enzyme that preferentially colocalizes with autophagosomes and is involved in the maturation of autophagosomes to autolysosomes, which is the final step of autophagy. In organotypic brain slices from mice, PLD1 inhibition results in higher levels of insoluble hyperphosphorylated tau and p62 aggregates, a protein primarily degraded via autophagy. These data suggest PLD1 is a promising therapeutic target for AD with benefits in promoting autophagic flux and neuronal health. Ceracuity is developing a novel series of PLD1 activator compounds to promote autophagic flux in neurons and clearance of tau aggregates. Ceracuity’s approach offers a number of advantages over other means to enhance autophagic flux as a strategy to treat AD, such as the ability of the autophagy-lysosome pathway to clear large, oligomerized proteins found in AD, and the ability of PLD1 activators to increase the clearance of tau aggregates by upregulating autophagic flux. To achieve these goals, Ceracuity will identify and rank new chemistry starting points to diversify the pool of lead candidates from a library of ~150K compounds, and then define the in vivo efficacy of the top hit compounds in a tau mutant zebrafish model.

项目总结