更新于：2024-11-21

CS-6253

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

Cogpep

靶点

ABCA1

作用机制

ABCA1刺激剂(ATP结合盒转运蛋白A1刺激剂)

治疗领域

神经系统疾病心血管疾病内分泌与代谢疾病

在研适应症

阿尔茨海默症动脉硬化2型糖尿病

非在研适应症-

原研机构

University of California, Berkeley

在研机构

Tel-Aviv University

National Institute on Aging

Artery Therapeutics, Inc.

+ [1]

非在研机构-

最高研发阶段早期临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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序列信息

Sequence Code 15018039

关联

项与 CS-6253 相关的临床试验

NCT05965414 / Active, not recruiting早期临床1期

A Phase 1 Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers and in APOE4 Carriers

* Phase 1A SAD: Five or more cohorts of 8 healthy volunteers (HVs) will receive a single IV bolus injection of study drug or placebo. The first 4 cohorts will be male only. The last cohort will be repeated with the max safe dose of the previous cohorts in healthy elderly subjects (male and female of non childbearing potential, > 50years)
* Phase 1B MAD: Two or more cohorts of 8 male and female HVs will receive multiple (4) IV bolus injections of study drug or placebo every 72 hours.
* Phase 1 Subcutaneous SC Cohort: One cohort of 6 male and 6 female HVs will receive one SC injection of study drug.

开始日期2023-10-23

申办/合作机构

Artery Therapeutics, Inc.

[+1]

100 项与 CS-6253 相关的临床结果

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100 项与 CS-6253 相关的转化医学

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100 项与 CS-6253 相关的专利（医药）

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项与 CS-6253 相关的文献（医药）

2022-12-01·Alzheimer's Research & Therapy

Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys

Article

作者: Yassine, Hussein N ; Parks, Bryan A ; Smadi, Sabrina ; Johansson, Johannes ; Meuret, Cristiana ; Johansson, Jan O ; Xian, Haotian ; Noveir, Sasan D ; Martinez, Ashley E ; Kerman, Bilal E ; Kuklenyik, Zsuzsanna ; Zetterberg, Henrik ; Mack, Wendy J

Abstract Background Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer’s disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans.MethodsCS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models.ResultsFollowing CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aβ42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aβ42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids.ConclusionsTreatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain.

2019-06-01·Canadian Journal of Cardiology2区 · 医学

ABCA1 Agonist Mimetic Peptide CS-6253 Induces Microparticles Release From Different Cell Types by ABCA1-Efflux–Dependent Mechanism

2区 · 医学

Article

作者: Genest, Jacques ; Johansson, Jan O ; Hafiane, Anouar

BACKGROUNDSmall peptides based on the C-terminal domain of apo E have recently been proposed as ATP-binding cassette transporter A1 (ABCA1) agonist with therapeutic potential. Previous work has shown that a novel synthetic peptide, CS-6253, acts synergistically with apolipoprotein A-I or alone to generate high-density lipoprotein (HDL) particles; we have also shown that cells can release microparticles (50-350 nm in apparent diameter) in an ABCA1- and apolipoprotein A-I-dependent manner. The purpose of this study was to explore the ability of a novel synthetic peptide CS-6253 to induce microparticle release from various cell lines in the process of HDL biogenesis.METHODSThe effects of CS-6253 on microparticle formation through the ABCA1 transporter were examined in vitro using cell-based systems and pharmacologic manipulations.RESULTSIn cell-based systems combined with fast performance liquid chromatography and nano-sight-tracking analysis, we show that ABCA1 and CS-6253 mediate and increase the production of microparticles containing cholesterol. CS-6253 in baby hamster kidney cells not expressing ABCA1 (baby hamster kidney mock cells) did not alter cholesterol removal across the plasma membrane in the absence of ABCA1 expression even at high concentrations. We report that CS-6253 is not cytotoxic.CONCLUSIONSThe present study shows that CS-6253 generates cholesterol containing microparticles with size heterogeneity (100-350 nm) in an ABCA1-dependent manner. We show that microparticles contribute to cell cholesterol efflux from monocyte-macrophage cells. At high doses, CS-6253 is not able to extract cholesterol from cells not expressing ABCA1, indicating that CS-6253 requires ABCA1 cooperation for cholesterol mobilization. We conclude that CS-6253 is an ABCA1 agonist peptide that promotes cellular cholesterol efflux through HDL biogenesis and microparticle formation.

2016-10-04·Journal of Alzheimer's Disease3区 · 医学

ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies

3区 · 医学

Article

作者: Johansson, Jan O. ; Kayed, Rakez ; Bielicki, John K. ; Michaelson, Daniel M. ; Boehm-Cagan, Anat ; Liraz, Ori ; Bar, Roni

The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

100 项与 CS-6253 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床1期	西班牙	Artery Therapeutics, Inc.	2023-10-23
阿尔茨海默症	临床1期	西班牙	National Institute on Aging	2023-10-23
动脉硬化	临床前	美国	University of California, Berkeley	-
动脉硬化	临床前	美国	Artery Therapeutics, Inc.	-
2型糖尿病	临床前	美国	University of California, Berkeley	-