Development of CDK5-p25 modulator to treat Alzheimer's Disease and Frontotemporal Dementia

开发治疗阿尔茨海默病和额颞叶痴呆的 CDK5-p25 调节剂

基本信息

批准号：
10023553
负责人：
Sanjeev Thohan
金额：
$ 23.63万
依托单位：
COGENTIS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023553
关键词：
Aftercare Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease therapy Amino Acids Amyloid beta-Protein Precursor Animals Autopsy Biological Assay Blood Blood - brain barrier anatomy Blood Tests Brain CDK5 gene Cell Death Cells Clinic Clinical Clinical Trials Cognitive Cognitive deficits Companions Data Dementia Deposition Development Disease Disease model Dose Drug Kinetics Enzyme-Linked Immunosorbent Assay Fluorescein Fluorescein-5-isothiocyanate Frontotemporal Dementia Funding Genetic Goals Hyperactive behavior Immunohistochemistry Infiltration Inflammation Kinetics Label Laboratories Legal patent Length Licensing Link Mass Spectrum Analysis Measurement Measures Mediating Microglia Microscopy Mission Modeling Mus National Institute of Neurological Disorders and Stroke Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Patients Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phosphotransferases Physiological Primates Publishing Reporting Research Contracts Resolution Risk Rivers Scheme Senile Plaques Small Business Innovation Research Grant Societies Testing Therapeutic Time Toxic effect United States National Institutes of Health Universities Variant Western Blotting biomarker development blood-brain barrier crossing blood-brain barrier penetration drug development exosome experimental study fluorophore genome wide association study human stem cells kinase inhibitor lead optimization motor deficit motor disorder mouse model neuroinflammation neurotoxic nonhuman primate novel novel therapeutics peptide drug peripheral blood pharmacodynamic model pharmacokinetics and pharmacodynamics pre-clinical preservation prevent programs protein protein interaction response tau Proteins tau-protein kinase

项目摘要

Post-mortem evidence shows that CDK5, a major kinase for tau and amyloid precursor protein, is hyperactive in the brains of patients with AD. Multiple genome wide association studies link CDK5 alleles to AD. Elegant genetic mouse(5xFAD) and human stem cell-derived neuron studies demonstrate the CDK5 hyperactivity is required (rather than just a correlation) for progression of AD pathology. CDK5 is widely considered an ideal target for AD therapy because it is only active in neurons, and it acts upstream of tau hyperphosphorylation, amyloid plaque deposition, and inflammation. Accordingly, several major pharma companies targeted CDK5 with kinase inhibitor programs. These companies eventually discontinued their CDK5 programs before reaching the clinic due to off-target toxicity. CDK5 hyperactivity was mediated by its interaction with p25, a cleavage product of p35 which is uniquely expressed in the brain. Dr. Harish Pant of NINDS, the original discoverer of CDK5 activity, circumvented this problem, using an unprecedented approach to kinase pharmacobiology. Rather than developing a kinase inhibitor, Dr. Pant developed and patented TFP5, a 34 amino acid peptide therapeutic that disrupts CDK5-p25 interaction in the brain, blocking toxic hyperactivity while preserving normal levels of activity and avoiding off target effects. Cogentis Therapeutics was formed at Johns Hopkins University upon winning the NIH NeuroStartup Challenge and licensing TFP5 from NINDS. Our aim is to de-risk and develop TFP5 so pharmaceutical companies will be willing to test the asset in large-scale clinical trials. TFP5, thus far, has been shown to enter the 5xFAD mouse model brain (via microscopy with fluorophore-labeled drug), engage its target, normalize tau hyperphosphorylation, reduce plaques and inflammation (proof of principle), and reverse cognitive/motor dysfunction. Although TFP5 has an extensive data package in multiple mouse models, there are several key preclinical milestones that must be achieved before a major pharmaceutical company(s) will be willing to invest in this asset to develop a product for the treatment of neurodegenerative disease. These milestones were discussed at length with representatives from multiple pharmaceutical companies and they include: 1) verification that the drug crosses the blood-brain-barrier by mass spectrometry with preliminary brain vs blood pharmacokinetic ratios, 2) Higher-resolution dosing schemes and target engagement pharmacodynamic profiles, and 3) evidence in nonhuman primates for blood brain barrier penetration/target engagement. Phase 1 of our SBIR will achieve the first 2 items, and if successful, we will apply for phase 2 to fund the third item and prepare for clinical trials.

事后证据表明，CDK5是tau和淀粉样蛋白前体蛋白的主要激酶，是 AD患者大脑中的多动。多个基因组范围的研究研究将CDK5等位基因与广告。优雅的遗传小鼠（5xFAD）和人类干细胞衍生的神经元研究证明了CDK5 需要多动症（而不仅仅是相关性）以进行AD病理的发展。 CDK5广泛被认为是AD疗法的理想靶标，因为它仅在神经元中活跃，并且在Tau的上游起作用高磷酸化，淀粉样菌斑沉积和炎症。因此，几个主要制药公司将CDK5瞄准了激酶抑制剂计划。这些公司最终中断了 CDK5计划由于脱靶毒性而到达诊所之前。 CDK5多动症是由其介导的与p25的相互作用，p25是p35的裂解产物，在大脑中唯一表达。 Harish Pant博士 CDK5活动的原始发现者Ninds使用前所未有的方法绕过了这个问题进行激酶药物学。 Pant博士不是开发和专利的TFP5，而不是开发激酶抑制剂，而是 34个氨基酸肽疗法，可破坏大脑中CDK5-P25的相互作用，阻塞有毒的多动症同时保留正常的活动水平并避免目标效应。 Cogentis Therapeutics赢得了NIH Neurostartup，在Johns Hopkins大学成立 NINDS的挑战和许可TFP5。我们的目的是脱离风险和开发TFP5 SO Pharmaceutical 公司将愿意在大规模临床试验中测试资产。到目前为止，TFP5已显示已进入 5xFAD小鼠模型大脑（通过荧光团标记的药物显微镜）接合其靶标，使Tau正常化高磷酸化，减少斑块和炎症（原理证明）以及反向认知/运动功能障碍。尽管TFP5在多个鼠标模型中具有广泛的数据包，但有几个关键必须在一家大型制药公司之前实现的临床前里程碑将愿意投资在此资产中，开发用于治疗神经退行性疾病的产品。这些里程碑是与来自多家制药公司的代表进行了详细讨论，其中包括：1）验证该药物是否会通过质谱与初步脑与血液跨越血脑屏障药代动力学比，2）高分辨率给药方案和目标参与药效学剖面和3）非人类灵长类动物的证据表明血脑屏障渗透/目标参与。阶段1 我们的SBIR将实现前两个项目，如果成功，我们将申请第二阶段以资助第三项，并准备临床试验。