Optimization of a Chemokine Receptor Antagonist Peptide as a Synapse Protecting Treatment for Neurodegeneration in Alzheimer's Disease

趋化因子受体拮抗剂肽的优化作为阿尔茨海默病神经变性的突触保护治疗

• 批准号: 10322074
• 负责人: Michael R Ruff
• 金额: $ 49.99万
• 依托单位: CREATIVE BIO-PEPTIDES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322074
• 关键词: AMD3100; Actins; Aftercare; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amides; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Architecture; Astrocytes; Atrophic; Biological Assay; Biological Availability; Brain; Brain Injuries; Brain scan; CCR5 gene; Caregivers; Cell Nucleus; Cells; Classification; Clinical; Cognitive; Cognitive deficits; Complex; DLG4 gene; Data; Dementia; Dendrites; Dendritic Spines; Development; Distal; Dose; Drug Kinetics; Drug Targeting; Early Intervention; Evaluation; Family; Female; Formulation; Functional disorder; Future; Growth Cones; HIV-associated neurocognitive disorder; Half-Life; Hippocampus (Brain); Human; Impaired cognition; Individual; Infiltration; Inflammatory; Innate Immune System; Lead; Length; Lesion; Link; Maximum Tolerated Dose; Measures; Mediating; Memory Loss; Morphology; Mus; NADPH Oxidase; Natural regeneration; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Nose; Nuclear Antigens; Oral; Oxidative Stress; Peptides; Persons; Pharmaceutical Preparations; Phase; Physiological; Plasma; Play; PrP; Rapid screening; Rattus; Receptor Activation; Rod; Role; Safety; Sampling; Signal Pathway; Stains; Stroke; Synapses; Testing; Toxicokinetics; United States National Institutes of Health; Vertebral column; Wild Type Mouse; age related cognitive disorder; aged; amyloid formation; analog; axonal sprouting; chemokine; chemokine receptor; cofilin; cognitive benefits; cytokine; density; dentate gyrus; dimer; drug development; functional decline; functional disability; immunoreactivity; improved; lead candidate; lead optimization; male; monocyte; mouse model; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; normal aging; novel therapeutic intervention; novel therapeutics; peptide analog; phase II trial; pre-clinical; preservation; prevent; receptor; response; synaptic function; trafficking

7. Project Summary AD In response to PAS-19-319, Creative Bio-Peptides, Inc. proposes a novel therapeutic approach to protect and restore synapses in Alzheimer’s Disease (AD) by blocking multiple chemokine receptors that promote synapse loss and inhibit their regeneration. Functional impairment in AD results from loss of neuronal spines and dendrites, preceding and independent of neuronal death. Cofilin-actin rods (rods) are a 1:1 complex of actin and cofilin whose formation is linked to a cellular prion protein (PrPC) and NADPH oxidase (NOX)-dependent signaling pathway and represents an early AD pathology. Rods form in neurites under conditions of energetic and oxidative stress, such as occur in neuroinflammation, and lead to neurite distal atrophy. Synapse function declines in neurites in which rods have formed compared neurites without rods from the same neuron and rods are significantly increased in animal models of AD and in human AD brain. Conversely, cognitive deficits in mouse models of AD are alleviated by decreasing cofilin rods in neurons. Cofilin plays important roles in dendritic spine dynamics and receptor trafficking and the sequestering of cofilin into rods is detrimental to synaptic function. Our preliminary data shows that new oral, stable and rapidly brain penetrant peptide analogs of the clinical use multi-chemokine receptor antagonist (mCRA) DAPTA (Dala1-peptide T-amide) inhibit the formation of Aβd/t (1 nM)-induced cofilin-actin rods and are neuroprotective. DAPTA reduced microglial activation in the dentate gyrus, prevented cortical neuronal loss in NBM-lesioned aged animals and promoted robust sprouting of axons and synapse regeneration in animals. In multiple phase 2 trials conducted by the NIH on subjects with HIV-associated neurocognitive disorders (HAND), DAPTA normalized functional brain scans and reversed cognitive deficits in phase 2 trials by chemokine receptor blocking mechanisms related to preventing cofilin rod formation and protecting synapses. The synapse and neurite extending effects of chemokine blockade were recently also shown for maraviroc in brain injuries confirming chemokine receptors as translational targets for drug development. DAPTA was safe in over 600 persons, some for as long as ten years however was not stable as a nasal spray formulation. It took us many years to create new stable oral analogs of DAPTA with better brain entry and long half-life and now propose to optimize a lead oral peptide for synapse protecting and restoring benefits in AD by determining the EC50 values for four oral peptides to inhibit formation of Aβd/t-induced cofilin rods compared to approved CRA’s maraviroc and AMD3100 in primary mouse hippocampal neuronal cultures. We will further optimize the neuroprotective effects of peptides in Aβd/t-treated neurons through quantifiable morphological and architectural assessments of synapse morphology. Once we have identified the optimized peptide, we will determine the safety and toxicokinetic profile and confirm brain entry as a prelude to future IND- enabling studies.

7。项目摘要广告 为了回应PAS-19-319，Creative Biopeptides，Inc。提出一种新型的保护和保护和 通过阻断促进突触的多种趋化因子受体来恢复阿尔茨海默氏病（AD）的突触 损失并抑制其再生。 AD的功能障碍导致神经元棘的丧失和 树突，前面并且独立于神经元死亡。 cofilin-肌动蛋白杆（杆）是肌动蛋白的1：1络合物， Cofilin的形成与细胞prion蛋白（PRPC）和NADPH氧化物（NOX）依赖性相关的Cofilin 信号通路并代表早期的AD病理。在能量条件下，神经运动中形成了杆 和氧化应激，例如在神经炎症中发生，并导致远端萎缩。突触功能 在神经杆上形成的神经运动中的下降，比较了没有来自同一神经元和杆的杆的神经运动 AD和人类AD大脑的动物模型显着增加。相反，认知缺陷 通过减少神经元中的Cofilin棒来减少AD的小鼠模型。 Cofilin在树突状 脊柱动力学和受体运输以及cofilin隔离到杆上是不利于突触 功能。我们的初步数据表明，新的口头，稳定和快速的脑穿透性胡椒类似物 临床用途多变态分体受体拮抗剂（MCRA）DAPTA（DALA1肽T-酰胺）抑制形成 AβD/T（1 nm）诱导的cofilin-actin棒的杆子，具有神经保护作用。 DAPTA降低了小胶质激活 齿状回，预防NBM衰老的动物的皮质神经元丧失并促进强大的萌芽 轴突和动物突触再生。在多个阶段2试验中，NIH对受试者进行了 HIV相关的神经认知障碍（手），DAPTA归一化功能性脑扫描并反转 认知在第二阶段试验中通过趋化因子接收器阻断机制与防止Cofilin Rod有关的定义 形成和保护突触。趋化因子阻滞的突触和神经蛋白神经蛋白的扩展作用是 最近在脑损伤中也显示了Maraviroc 药物开发。 DAPTA在600多人中是安全的，有些人长达十年不稳定 作为鼻喷雾配方。我们花了很多年的时间才能用更好的大脑创建新的稳定口服类似物 进入和长期寿命，现在提议优化铅口腔胡椒粉以保护和恢复 通过确定四个口服胡椒体的EC50值抑制AβD/T诱导的Cofilin的益处 与批准的CRA的Mariviroc和Amd3100相比，在原发性小鼠海马神经元培养物中。 我们将通过可量化的AβD/T处理神经元中Petides在AβD/T处理的神经元中的神经保护作用 突触形态的形态和建筑评估。一旦我们确定了优化的 肽，我们将确定安全性和有毒动力学特征，并确认大脑进入未来的前奏 启用研究。

项目成果

Chemokine Receptor Antagonists Prevent and Reverse Cofilin-Actin Rod Pathology and Protect Synapses in Cultured Rodent and Human iPSC-Derived Neurons.

• DOI: 10.3390/biomedicines12010093
• 发表时间: 2024-01-01
• 期刊: BIOMEDICINES
• 影响因子: 4.7
• 作者: Kuhn, Thomas B.;Minamide, Laurie S.;Tahtamouni, Lubna H.;Alderfer, Sydney A.;Walsh, Keifer P.;Shaw, Alisa E.;Yanouri, Omar;Haigler, Henry J.;Ruff, Michael R.;Bamburg, James R.
• 通讯作者: Bamburg, James R.

Characterization of a Human Neuronal Culture System for the Study of Cofilin-Actin Rod Pathology.

• DOI: 10.3390/biomedicines11112942
• 发表时间: 2023-10-31
• 期刊: Biomedicines
• 影响因子: 4.7