Selective Activators of Nrf2 for Neurodegenerative Disease

Nrf2 选择性激活剂治疗神经退行性疾病

• 批准号: 10758091
• 负责人: Paul Anthony Bertin
• 金额: $ 24.67万
• 依托单位: GROVE BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10758091
• 关键词: Address; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Antibodies; Antioxidants; Architecture; Avidity; Binding; Biochemical; Biological Products; Biological Response Modifier Therapy; Biotechnology; Brain; Cells; Cellular Assay; Charge; Clinic; Clinical; Complex; Cytoplasm; Data; Development; Disease; Disease model; Drug Targeting; Endosomes; Equilibrium; Erythroid; Exhibits; Functional disorder; GATA1 gene; Gene Expression; Genes; Goals; Half-Life; Healthcare Systems; In Vitro; Individual; Inflammation; Intervention; Kinetics; Lead; Length; Libraries; Ligase; Malignant Neoplasms; Medical; Modality; Modeling; Mus; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Translocation; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Patient-Focused Outcomes; Penetration; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Polymers; Positioning Attribute; Property; Proteins; Reporter Genes; Response Elements; Role; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Specificity; System; Tertiary Protein Structure; Therapeutic; Therapeutic Effect; Transgenic Organisms; Treatment outcome; Ubiquitination; Universities; Variant; Vertebral column; density; genetic regulatory protein; improved; in vivo; ineffective therapies; inhibitor; lead candidate; monomer; mouse model; nervous system disorder; next generation; novel; nuclear factor-erythroid 2; polymerization; programs; protein complex; protein protein interaction; proteostasis; public health relevance; response; scaffold; sensor; small molecule; success; targeted treatment; tau Proteins; technology platform; tool; transcription factor; ubiquitin-protein ligase

Protein-like polymers (PLPs) are next generation biotherapeutics with the potential to improve treatment outcomes for patients suffering from devastating neurodegenerative diseases. We have developed a lead PLP that disrupts the Keap1-Nrf2 intracellular protein-protein interaction (PPI) that restricts the therapeutic activity of Nrf2 (nuclear factor-erythroid factor 2-related factor 2), a validated transcription factor target that regulates a system of hundreds of genes involved in protective responses against oxidative stress and proteostasis that has eluded selective intervention. This application is directly relevant to Alzheimer’s Disease/Alzheimer’s Disease Related Dementias (AD/ADRD) since enhanced Nrf2 activation in the brains of multiple mouse models of AD demonstrate significantly reduced AD associated pathology in the mice. The reduction in beta-amyloid levels, plaque numbers, and tau pathology in these models attest to the importance of Nrf2 in mitigating AD/ADRD. Thus, the studies outline in this proposal will lead to the development of completely novel Nrf2 activating biologics that could be used in the treatment of AD/ADRD. Preliminary data demonstrates that PLPs activate Nrf2 in primary cortical neurons in vitro and exhibit a 4d half-life in vivo. Our central objective is to optimize our PLP lead to improve its ability to activate Nrf2 in cells by tuning its architecture to balance its biochemical potency and cellular entry. Information from these studies will be used to nominate an advanced lead for follow-on Phase II pharmacodynamic studies in ARE-hPAP transgenic reporter and AD (APPK595N,M596L/PS1∆E9) models to nominate a development candidate, which will be the focus of our Phase II plan.

蛋白质样聚合物（PLPs）是下一代生物治疗药物，有可能改善患有毁灭性神经退行性疾病的患者的治疗结果。我们已经开发了一种先导PLP，它可以破坏Keap 1-Nrf 2细胞内蛋白质-蛋白质相互作用（PPI），这种相互作用限制了Nrf 2（核因子-红细胞因子2相关因子2）的治疗活性，Nrf 2是一种经过验证的转录因子靶点，可调节数百个基因的系统，这些基因参与了对氧化应激和蛋白质稳态的保护性反应，而这种保护性反应逃避了选择性干预。本申请与阿尔茨海默氏病/阿尔茨海默氏病相关痴呆（AD/ADRD）直接相关，因为在多种AD小鼠模型的脑中增强的Nrf 2活化表明在小鼠中显著降低的AD相关病理。这些模型中β-淀粉样蛋白水平、斑块数量和tau病理学的降低证明了Nrf 2在减轻AD/ADRD中的重要性。因此，本提案中概述的研究将导致开发可用于治疗AD/ADRD的全新Nrf 2激活生物制剂。初步数据表明，PLPs在体外激活原代皮层神经元中的Nrf 2，并在体内表现出4d的半衰期。我们的中心目标是优化我们的PLP导致通过调整其结构来平衡其生化效力和细胞进入来提高其在细胞中激活Nrf 2的能力。来自这些研究的信息将用于在ARE-hPAP转基因报告基因和AD（APPK 595 N，M596 L/PS1 E19）模型中提名后续II期药效学研究的高级领导者，以提名开发候选者，这将是我们II期计划的重点。