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.项目总结AD 作为对PAS-19-319的回应，Creative Bio-多肽公司提出了一种新的治疗方法来保护和 通过阻断促进突触的多个趋化因子受体恢复阿尔茨海默病(AD)的突触 丧失并抑制它们的再生。阿尔茨海默病的功能损害是由于神经元脊椎和 树突，先于神经元死亡且独立于神经元死亡。粘附素-肌动蛋白棒(杆)是肌动蛋白和肌动蛋白的1：1复合体。 Cofilin的形成与细胞内的PrPC和NADPH氧化酶(NOX)相关 信号转导途径，代表AD的早期病理。在高能条件下，轴突中形成杆状结构 而氧化应激等则发生在神经炎症中，并导致轴突远端萎缩。突触功能 有杆状突起的神经突起与没有来自相同神经元和杆状突起的突起相比下降 在阿尔茨海默病动物模型和人类阿尔茨海默病脑中显著增加。相反，认知缺陷 通过减少神经元中的cofilin杆，可以缓解小鼠的AD模型。粘附素在树突状细胞中的重要作用 脊椎动力学和受体运输以及将cofilin隔离到视杆中对突触有害 功能。我们的初步数据显示，新的口服、稳定和快速的脑透性多肽类似物 临床使用多趋化因子受体拮抗剂(MCRA)DAPTA(Dala1肽T-酰胺)抑制其形成 Aβd/t(1 NM)诱导的粘连蛋白-肌动蛋白棒，具有神经保护作用。DAPTA减少小胶质细胞的激活 齿状回，防止NBM损伤老年动物皮质神经元的丢失，并促进健壮的萌发 动物的轴突和突触再生。在美国国立卫生研究院进行的多个2期试验中，受试者患有 HIV相关神经认知障碍(手)，DAPTA功能扫描正常化并逆转 趋化因子受体阻断机制在2期试验中的认知缺陷与防止Cofilin棒相关 形成和保护突触。趋化因子阻断对突触和轴突的延伸作用 最近还显示马拉韦罗用于脑损伤，证实趋化因子受体是脑损伤的翻译靶点 药物开发。DAPTA在600多人中是安全的，有些人长达十年，但并不稳定 作为鼻腔喷雾剂配方。我们花了许多年的时间来创造出大脑更好的新的稳定的DAPTA口服类似物 进入和较长的半衰期，现在建议优化一种用于突触保护和恢复的先导口服多肽 通过测定四种口服多肽抑制Aβd/t诱导的纤连蛋白形成的EC50值在AD中的益处 与CRA批准的马拉韦罗和AMD3100在原代小鼠海马神经元培养中的比较。 我们将进一步优化多肽对Aβd/t处理神经元的神经保护作用 突触形态的形态和构筑评估。一旦我们确定了优化的 多肽，我们将确定其安全性和毒代动力学特征，并确认脑进入是未来IND的前奏。 使研究成为可能。

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