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. 项目概要 AD 为了响应 PAS-19-319，Creative Bio-Peptides, Inc. 提出了一种新的治疗方法来保护和 通过阻断多种促进突触的趋化因子受体来恢复阿尔茨海默病 (AD) 的突触 AD 中的功能障碍是由于神经棘的丢失和抑制而导致的。 树突，位于神经元死亡之前且独立于肌动蛋白-肌动蛋白杆（杆）是肌动蛋白和肌动蛋白的 1:1 复合物。 cofilin 的形成与细胞朊病毒蛋白 (PrPC) 和 NADPH 氧化酶 (NOX) 依赖性相关 信号通路并代表了早期 AD 病理学在能量条件下在神经突中形成。 和氧化应激，例如发生在神经炎症中，并导致神经突远端萎缩。 与来自相同神经元和杆的没有杆的神经突相比，已形成杆的神经突减少 在 AD 动物模型和人类 AD 大脑中，认知缺陷显着增加。 小鼠 AD 模型通过减少神经元中的丝丝蛋白丝切蛋白棒而得到缓解，丝丝蛋白丝切蛋白在树突中发挥重要作用。 脊柱动力学和受体运输以及将丝动蛋白隔离到杆中对突触不健康 我们的初步数据表明，新的口服、稳定且快速的脑渗透肽类似物。 临床使用多趋化因子受体拮抗剂（mCRA）DAPTA（Dala1-肽T-酰胺）抑制形成 Aβd/t (1 nM) 诱导的丝切蛋白-肌动蛋白棒具有神经保护作用，DAPTA 可减少小胶质细胞的激活。 齿状回，防止 NBM 损伤的老年动物皮质神经元损失并促进强健的发芽 NIH 对动物的轴突和突触再生进行了多项 2 期试验。 HIV 相关神经认知障碍 (HAND)、DAPTA 标准化功能性脑扫描和逆转 与预防 cofilin rod 相关的趋化因子受体阻断机制导致的 2 期试验中的认知缺陷 趋化因子阻断的突触和神经突延伸作用。 最近还显示马拉韦罗在脑损伤中的作用，证实趋化因子受体是 药物开发对 600 多人来说是安全的，有些长达十年，但并不稳定。 作为一种鼻喷雾剂配方，我们花了很多年的时间才创造出具有更好大脑功能的新的稳定的 DAPTA 口服类似物。 进入和长半衰期，现在建议优化用于突触保护和恢复的先导口服肽 通过确定四种口服肽抑制 Aβd/t 诱导的丝切蛋白形成的 EC50 值，了解 AD 的益处 在原代小鼠海马神经元培养物中将棒与批准的 CRA 的 maraviroc 和 AMD3100 进行比较。 我们将通过可量化的方法进一步优化肽对 Aβd/t 处理的神经元的神经保护作用 一旦我们确定了优化的形态结构和突触形态的评估。 肽，我们将确定安全性和毒代动力学特征，并确认大脑进入，作为未来 IND-的前奏 赋能研究。

项目成果

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

用于研究丝切蛋白-肌动蛋白杆病理学的人类神经元培养系统的表征。

• 发表时间: 2023-10-31
• 影响因子: 4.7
• 作者: Tahtamouni, Lubna H;Alderfer, Sydney A;Kuhn, Thomas B;Minamide, Laurie S;Chanda, Soham;Ruff, Michael R;Bamburg, James R
• 通讯作者: Bamburg, James R

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

趋化因子受体拮抗剂可预防和逆转肌丝蛋白丝动蛋白-肌动蛋白杆病理学并保护培养的啮齿动物和人类 iPSC 衍生神经元中的突触。

• 发表时间: 2024-01-01
• 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