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Regulation of Exosome Secretion as a novel therapeutic approach for Alzheimer's Disease

外泌体分泌调节作为阿尔茨海默病的新型治疗方法

基本信息

批准号：
10183123
负责人：
Barbara Stauch Slusher
金额：
$ 49.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183123
关键词：
3xTg-AD mouse Abeta synthesis Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Behavioral Biochemical Biochemistry Biological Assay Brain Cells Ceramides Chemical Structure Chemicals Chemistry Chronic Clinical Clinical Trials Cognition Cognitive Cognitive deficits Collaborations Czech Republic Disease Disease Progression Drug Discovery Groups Drug Kinetics Enzymes Etiology Exhibits Future Genetic Goals Human Hydrolysis In Vitro Institutes Laboratories Link Liver Microsomes Membrane Metabolic Modeling Molecular Mus Neuroglia Neurology Neurons Oxidative Stress Patients Penetration Pharmaceutical Preparations Pharmacology Play Regulation Role Senile Plaques Series Serum Signaling Molecule Solubility Source Sphingomyelinase Sphingomyelins Structure-Activity Relationship Therapeutic Toxic effect Translational Research Up-Regulation Work abeta accumulation base drug discovery exosome follow-up high throughput screening improved in vivo inhibitor/antagonist lipid metabolism mouse model neuroinflammation new therapeutic target novel therapeutic intervention pre-clinical preclinical study prevent screening small molecule libraries tau Proteins

项目摘要

Project abstract Current available treatments for Alzheimer's disease (AD) only provide modest amelioration of cognitive and behavioral decline. Recent clinical trials targeting amyloid-β (Aβ) production or clearance did not show efficacy prompting a reexamination of approaches to AD treatment. Brains from AD patients have been shown to exhibit accumulation of ceramide, a signaling molecule and an integral component of exosomal membranes. One major source of ceramide is through the hydrolysis of sphingomyelin catalyzed by neutral sphingomyelinase 2 (nSmase2). Even though transient increases in ceramide through nSMase2 upregulation are part of normal brain functioning, experimental evidence indicates that chronic nSMase2 upregulation results in negative effects including neuroinflammation and oxidative stress. Recent studies also implicate nSMase2 in both Aβ aggregation and tau protein propagation through exosome secretion from neurons and glial cells. Moreover, inhibition of exosome synthesis by genetic or pharmacological inhibition of nSMAse2 significantly reduced Aβ aggregation and tau propagation both in vitro and in vivo thus opening a new avenue for AD therapeutics. While nSmase2 is emerging as an important player in AD etiology, the current armamentarium of nSMase2 inhibitors is inadequate to develop potential treatments. Currently available inhibitors have limitations including low potency (IC50's in µM level), poor solubility, and limited brain penetration. In order to address these limitations, we developed a human nSMase2 high throughput screening assay and screened over 350,000 compounds which led to the identification of several hits belonging to different chemical series. Early optimization of two of these hits from different chemical series led to two potent compounds with IC50s of 50 and 300 nM. Both of these compounds were confirmed as inhibitors of exosome release and exhibited good pharmacokinetic profiles and brain penetration (AUCbrain/AUCplasma = 0.27 and 0.6). The objective of this proposal is to further optimize these nSMase2 inhibitors to identify a potent, selective, brain penetrable candidate to carry out proof of concept before future IND enablement studies and ultimately for treatment of patients with AD. Aim 1 is to conduct structure-activity relationship studies to improve potency. Aim 2 is to characterize the compounds from aim 1 for functional inhibition of exosome release, metabolic stability, selectivity and in vivo pharmacokinetics. Aim 3 is to carry out in vivo proof of concept studies by evaluating selected compounds in the 3xTg mouse model of AD. The work proposed involves a novel therapeutic target which is mechanistically distinct from previous efforts in AD treatment, has the potential of addressing disease progression, and exploits two newly discovered chemical series of drug-like nSMase2 inhibitors.

项目摘要