Development of a Synthetic, Cell-Permeable Peptide for the Inhibition of CDK5-p25 Hyperactivity in Amyotrophic Lateral Sclerosis

开发一种合成的细胞渗透性肽，用于抑制肌萎缩侧索硬化症中 CDK5-p25 的过度活跃

• 批准号: 10490885
• 负责人: John Kent Werner
• 金额: $ 102.73万
• 依托单位: COGENTIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490885
• 关键词: ALS patients; Address; Advanced Development; Age; Amyotrophic Lateral Sclerosis; Autopsy; Biological Assay; Biological Markers; Brain; Cell Line; Cells; Cellular Stress; Cerebrospinal Fluid; Clinical Research; Companions; Cyclin-Dependent Kinase 5; Development; Disease; Dose; Etiology; Exhibits; FDA approved; Future; Gait; Generations; Glutamates; Human; Hyperactivity; Inflammatory; Inherited; Kyphosis deformity of spine; Life Expectancy; Link; Longevity; Mechanical ventilation; Mechanics; Modeling; Motor; Mus; Muscle Fatigue; Muscle Weakness; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurofilament-L; Neurons; Onset of illness; Paralysed; Pathogenicity; Pathologic; Patients; Peptides; Performance; Permeability; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Phosphotransferases; Quality of life; Research; Riluzole; Risk Factors; Safety; Sampling; Small Business Innovation Research Grant; Spinal Cord; Subgroup; Therapeutic; Time; Titrations; Toxic effect; Toxicant exposure; Tracheostomy procedure; Work; amyotrophic lateral sclerosis therapy; base; clinical decision support; clinical decision-making; clinically relevant; commercialization; daily functioning; design; disorder control; drug development; effective therapy; exosome; improved; induced pluripotent stem cell; inflammatory marker; inhibitor; molecular subtypes; mouse model; neurofilament; novel therapeutics; patient subsets; phenylmethylpyrazolone; pre-clinical; preclinical study; preservation; protective effect; protein TDP-43; protein complex; protein function; relating to nervous system; respiratory; response; rho; sporadic amyotrophic lateral sclerosis; tau Proteins; therapeutic target; tool; treatment group; treatment strategy

PROJECT SUMMARY—In this Direct-to-Phase II SBIR application, Cogentis Therapeutics proposes to advance the development of CT526, a synthetic, cell-permeable peptide inhibitor of pathogenic CDK5-p25 as a treatment for neurodegeneration in amyotrophic lateral sclerosis (ALS). Cogentis has shown that CT526 normalizes the pathological activity of CDK5 in a mouse model of ALS while preserving essential CDK5 functionality, but additional work is needed to characterize its performance in phenotypically diverse mouse and clinically relevant human iPSC models. In addition, companion biomarkers are needed to track early responsiveness to CT526 in preclinical / clinical studies and to eventually support clinical decision-making, including drug titration. Given that the two FDA-approved drugs for ALS only provide modest benefit, further development and commercialization of CT526 and its companion biomarkers may substantially advance drug therapy for ALS, potentially providing the first treatment that slows, stops, or reverses neurodegeneration and its devastating effects on patient quality of life and survival. Aim 1. Demonstrate CT526 efficacy in a phenotypically diverse mouse model of ALS. Milestones: In the treatment group, 1) Demonstrate significant delay in disease onset, prolonged lifespan, and/or improved gait and kyphosis score progression; 2) Demonstrate normalization of CDK5 hyperactivity phenotype and p25 generation within 10% of the wildtype control level; 3) Demonstrate reduction of P-TDP43 and NF-L in cerebrospinal fluid; and 4) Demonstrate reduction of P-TDP43 and inflammatory markers in spinal cord. (P<0.05 for all differences.) Aim 2. Demonstrate the protective effect of CT526 in human iPSCs from patients with the most common molecular subtype of ALS. Milestones: 1) Validate CDK5 phenotype in iPSC cell lines by demonstrating ≥ 20% increase in CDK5 hyperactivity or ≥ 20% or more increase in p25/p35 ratio in ALS vs. healthy donor iPSCs; 2) Demonstrate dose-responsive protection of iPSCs in glutamate toxicity assays when treated with CT526. Aim 3. Characterize the response of neural-derived exosome (NDE)-based biomarkers to CT526. Milestones: 1) Demonstrate ≥ 20% increase in any of the CDK5 activity readouts in any subgroup of ALS postmortem brains compared to non-ALS age-matched controls. 2) Categorize ALS patient subtypes by CDK5 hyperactivity and degree of change in biomarkers. 3) Correlate biomarkers from postmortem brain and from NDE analysis with rho > 0.65, ≥ 20% difference between disease and control subgroups, and AUC ≥ 80%. 4) Detect ≥ 20% reduction in CDK5 hyperactivity-related NDE biomarkers in response to CT526 treatment of mouse/iPSC models in Aims 1 and 2. Impact—This project is expected to confirm CT526 efficacy in phenotypically diverse and clinically relevant models and identify an NDE-based biomarker(s) that can be used to track drug responsiveness in preclinical and clinical studies for an ALS therapeutic. In future work, Cogentis will a) leverage the biomarker(s) as a tool for optimizing CT526 dosing strategies and b) conduct IND-enabling safety, efficacy, and toxicity studies of CT526.

项目摘要 - 在此直接到相的II SBIR应用程序中 CT526的发展，一种致病性CDK5-P25的合成，可渗透的肽抑制剂 用于肌萎缩性侧索硬化症（ALS）中的神经变性。 Cogentis表明CT526归一化 CDK5在ALS的小鼠模型中的病理活性，同时保留必需的CDK5功能，但是 需要额外的工作来表征其在表型多样的小鼠中的表现和临床相关的 人IPSC模型。此外，需要伴侣生物标志物来跟踪对CT526的早期响应能力 临床前 /临床研究，最终支持临床决策，包括药物滴定。鉴于 ALS的两种FDA批准药物仅提供适度的收益，进一步的开发和商业化 CT526及其伴侣生物标志物可能会大大提高ALS的药物疗法，并有可能提供 减慢，停止或逆转神经变性及其对患者质量的毁灭性影响的第一种治疗方法 生活和生存。 AIM1。在ALS的表型多样性小鼠模型中证明CT526的有效性。 里程碑：在治疗组中，1）表现出疾病发作，寿命延长和/或 步态和Kyphosis得分的进展得到改善； 2）证明CDK5多动症表型的归一化 和p25在野生型控制水平的10％之内； 3）证明p-tdp43和nf-l的减少 脑脊液； 4）证明脊髓中P-TDP43和炎症标记的降低。 （p <0.05 AIM 2。 ALS最常见的分子亚型。里程碑：1）通过IPSC细胞系中的CDK5表型验证 证明CDK5多动症的增加≥20％或ALS vs的P25/p35比率增加了20％或更高。 健康的供体IPSC； 2）在谷氨酸毒性测定中对IPSC进行剂量响应性保护 用CT526处理。 AIM 3。表征基于神经衍生的外泌体（NDE）的生物标志物的响应 到CT526。里程碑：1）在任何子组中，任何CDK5活动读数中的任何一个子组中均显示≥20％ 与非ALS年龄匹配的对照相比，ALS验尸大脑相比。 2）按ALS患者亚型分类 CDK5多动症和生物标志物的变化程度。 3）将验尸大脑的生物标志物与 从NDE分析中，RHO> 0.65，疾病和对照亚组之间的差异≥20％，AUC≥80％。 4）检测CDK5多动相关的NDE生物标志物的≥20％，以响应CT526的处理 AIMS 1和2中的鼠标/IPSC模型。影响 - 该项目有望确认CT526的效率 表观上多样化和临床相关的模型，并识别可使用的基于NDE的生物标志物 跟踪ALS治疗的临床前和临床研究中的药物反应能力。在以后的工作中 a）将利用生物标志物作为优化CT526剂量策略的工具，b）进行指导 CT526的安全性，效率和毒性研究。