Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease

开发 MSUT2 纳米抗体来靶向阿尔茨海默病中的病理性 Tau 蛋白

• 批准号: 10363866
• 负责人: Brian C. Kraemer
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363866
• 关键词: Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Antibodies; Binding; Biological; Biological Products; Biological Response Modifier Therapy; Brain; Brain Diseases; Caenorhabditis elegans; Cell model; Cells; Clinical Trials; Dementia; Deposition; Development; Diagnostic; Disease; Epitopes; Exhibits; Future; Genes; Goals; High-Throughput Nucleotide Sequencing; Human; Immunization; Impaired cognition; Intervention; Intrabody; Investigation; Knowledge; Lead; Lesion; Measurement; Measures; Memory; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathologic; Pathology; Peptide Mapping; Phenotype; Poly(A)+ RNA; Predisposition; Production; Proteins; RNA; RNA Binding; RNA Recognition Motif; RNA-Binding Proteins; Severities; Tauopathies; Testing; Therapeutic; Toxic effect; Validation; Viral Vector; Work; adeno-associated viral vector; antagonist; base; biophysical properties; brain tissue; gene therapy; lead candidate; mouse model; nanobodies; neuroinflammation; neurotoxicity; novel; symptom treatment; tau Proteins; tau aggregation; tau-1; therapeutic candidate; therapeutic target; tool; translational study

Abstract In Alzheimer’s disease (AD) and related tauopathies, tau neuropathology correlates with severity of dementia. However, interventions for AD and AD related dementias (ADRDs) are limited to treatment of symptoms that do not directly alter tau pathology or the resultant neurodegeneration. This underscores the need for tau-targeted disease-modifying therapeutics. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain binding to poly(A) RNA, as deletion of the CCCH domain suppresses neurodegeneration in mouse models of tauopathy. The identification of single chain antibody or nanobody leads that inhibit MSUT2 from binding to poly(A) RNA will provide a biologic means of intervening against tauopathy. We hypothesize that biologic antagonism of MSUT2/poly(A) RNA-binding after onset of pathological tau deposition will reverse the toxic consequences of pathological tau. The specific aims of this proposal will develop potent and specific brain-penetrant biologic based approaches to target MSUT2 and use them to dissect the temporal and mechanistic relationship between MSUT2 activity and tauopathy. Completion of the project as proposed will also further demonstrate the importance of MSUT2 in tauopathy. This knowledge will set the stage for future translational studies by both generating MSUT2 specific lead biologic agents and further validating a novel candidate therapeutic target for intervention in tauopathy disorders.

抽象的 在阿尔茨海默氏病（AD）和相关的tauopathies中，tau神经病理学与严重程度有关 失智。但是，AD和AD相关痴呆症（ADRD）的干预措施仅限于治疗 不会直接改变tau病理或由此产生的神经退行性的症状。这 强调了对tau靶向疾病改良疗法的需求。我们的工作已经证明了 MSUT2控制着哺乳动物大脑中TAU毒性的神经元易感性。机制 tauopathy的MSUT2调节涉及MSUT2 CCCH结构域与poly（a）RNA的结合，AS CCCH结构域的缺失抑制了tauopathy小鼠模型中的神经退行性。 鉴定单链抗体或纳米病毒导致抑制MSUT2与poly（a）结合的识别 RNA将提供一种介入tauopathy的生物学方法。我们假设这种生物学 病理tau沉积发作后MSUT2/Poly（A）RNA结合的拮抗作用将 扭转病理tau的毒性后果。该提议的具体目的将发展 潜在的和特定的脑培训剂生物学的方法来靶向MSUT2，并将其用于 剖析MSUT2活性和tauopathy之间的暂时和机械关系。完成 在拟议的项目中，该项目还将进一步证明MSUT2在Tauopathy中的重要性。这 知识将通过产生MSUT2特定铅来为将来的翻译研究奠定基础 生物学剂并进一步验证新的候选治疗靶标，用于干预tauopathy 疾病。