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.

摘要