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.

尸检证据表明，CDK5（tau 和淀粉样前体蛋白的主要激酶）是 AD 患者的大脑过度活跃。多项全基因组关联研究将 CDK5 等位基因与广告。优雅遗传小鼠 (5xFAD) 和人类干细胞衍生的神经元研究证明了 CDK5 AD 病理的进展需要多动（而不仅仅是相关性）。 CDK5广泛被认为是 AD 治疗的理想靶点，因为它仅在神经元中活跃，并且作用于 tau 蛋白的上游过度磷酸化、淀粉样蛋白斑沉积和炎症。据此，几家主要制药公司公司通过激酶抑制剂项目针对 CDK5。这些公司最终都停产了由于脱靶毒性，CDK5 在到达临床之前进行了编程。 CDK5 过度活跃是由其介导的与 p25 相互作用，p25 是 p35 的裂解产物，在大脑中独特表达。 Harish Pant 博士 CDK5活性的最初发现者NINDS使用前所未有的方法规避了这个问题激酶药理学。 Pant 博士没有开发激酶抑制剂，而是开发了 TFP5 并获得了专利，一种 34 氨基酸肽治疗剂，可破坏大脑中 CDK5-p25 相互作用，阻止中毒性多动症同时保持正常的活动水平并避免脱靶效应。 Cogentis Therapeutics 在赢得 NIH NeuroStartup 奖后在约翰霍普金斯大学成立来自 NINDS 的挑战和许可 TFP5。我们的目标是降低风险并开发 TFP5，以便制药公司将愿意在大规模临床试验中测试该资产。到目前为止，TFP5已被证明可以进入 5xFAD 小鼠模型大脑（通过使用荧光团标记药物的显微镜观察），接合其靶标，使 tau 蛋白正常化过度磷酸化，减少斑块和炎症（原理证明），并逆转认知/运动功能障碍。尽管 TFP5 在多种鼠标模型中拥有广泛的数据包，但有几个关键点在大型制药公司愿意投资之前必须实现的临床前里程碑利用该资产开发一种治疗神经退行性疾病的产品。这些里程碑是与多家制药公司的代表进行了详细讨论，其中包括：1）通过初步脑部与血液的质谱分析验证药物可以穿过血脑屏障药代动力学比率，2) 更高分辨率的给药方案和目标参与药效学概况，以及 3) 非人类灵长类动物血脑屏障穿透/目标参与的证据。第一阶段我们的 SBIR 将实现前两项，如果成功，我们将申请第二阶段来资助第三项，为临床试验做准备。