Development of Aberrant Cdk5 imaging agent for early detection ofAlzheimer's disease pathology and treatment outcome measurement

开发异常 Cdk5 显像剂，用于早期检测阿尔茨海默病病理学和治疗结果测量

• 批准号: 10255458
• 负责人: Sudarshan C Upadhya
• 金额: $ 45万
• 依托单位: AESTAS PHARMA INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255458
• 关键词: Aftercare; Alzheimer disease detection; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; American; Amyloid; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Diseases; Calpain; Cause of Death; Cleaved cell; Clinical; Cyclin-Dependent Kinase 5; Dementia; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Differential Diagnosis; Disease; Disease Progression; Early Diagnosis; Early treatment; Event; Failure; Female; Guidelines; Hour; Impairment; Injections; Intervention; Lead; Link; Measurement; Measures; Memory impairment; Metabolic; Methods; Molecular Abnormality; Monitor; Mus; Neurofibrillary Tangles; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Patient Recruitments; Peptides; Pharmaceutical Preparations; Phase; Plasma; Positron-Emission Tomography; Prosthesis; Proteins; Rodent Model; Series; Small Business Innovation Research Grant; Stress; Study models; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Translational Research; Treatment Efficacy; Treatment outcome; United States National Institutes of Health; age group; aged; astrogliosis; asymptomatic Alzheimer' s disease; base; blood-brain barrier penetration; calpain inhibitor; diagnostic biomarker; drug candidate; early detection biomarkers; effective therapy; feasibility testing; first-in-human; fluorodeoxyglucose; follow-up; high risk population; imaging agent; in vitro Assay; in vivo; longitudinal positron emission tomography; male; mild cognitive impairment; mouse model; neuroimaging; neuroinflammation; neuron loss; neurotoxic; nonhuman primate; phase 1 study; potential biomarker; radioligand; radiotracer; screening; targeted treatment; tau Proteins; tau-1; tool; treatment comparison; uptake

Effective treatment for 5.5 million Americans with Alzheimer’s disease (AD) is desperately needed, as this irreversible brain disorder is the third leading cause of death in people aged 65 or older, and the leading cause of dementia. However, previous failed AD drug trials indicated that disease-modifying drugs need to be targeted to early-stages of AD to enable halting of the disease before significant damage has occurred. For this early-stage disease targeting therapeutic intervention, robust methods to detect early abnormal changes in the brain must be developed, highlighting an urgent need for a diagnostic biomarker for the early detection of AD pathology. Current AD biomarkers are mainly used at late-stage or for differential diagnosis of AD patients. Measurements of these biomarkers do not satisfy unmet clinical needs, as they do not offer effective diagnosis at the pre-symptomatic stage of disease progression (pre-symptomatic AD to Mild Cognitive Impairment (MCI) stage of AD). One potential biomarker that might facilitate early detection of early-stage pathology and disease progression in high-risk populations who could potentially develop AD is aberrant cyclin-dependent kinase 5 (aCdk5), which is generated during neurotoxic stress conditions. Previous studies demonstrated that induction of aCdk5 activity occurs prior to AD pathology. Aestas's diagnostic neuroimaging candidate targets disease- specific aCdk5, without interfering with normal functions. aCdk5 is considered a "unifying upstream" event in the development of AD pathologies. Aestas Pharma will develop an aCdk5 PET Imaging Agent, AP-251-X, as a first- in-class non-invasive biomarker detection agent for the early detection of AD pathology. This diagnostic approach has the potential to facilitate detecting AD pathology earlier than existing biomarkers and may also be used alongside aCdk5-based therapeutics or other drug candidates as a diagnostic imaging agent to measure the target engagement or efficacy of the therapeutics and monitor outcomes. AP-251-X links a radiotracer for neuroimaging to a small, highly specific aCdk5 inhibitory peptide (AP-PEP31) exclusively licensed from NIH. Aim 1 is to develop radioligands that are suitable as diagnostic imaging agents. We will apply these compounds to PET neuroimaging in both male and female AD model mouse brains for early detection of pathology. Aim 2 is to test the feasibility of a lead radioligand as a tool to measure the AD treatment outcome in the AD model. We will treat symptomatic and asymptomatic AD mice with an aCdk5 blocker drug and our radioligand as a tool to determine the reversal of AD-like pathologies. Successful completion of SBIR Phase I studies will result in Aestas Pharma developing an aCdk5-selective diagnostic for early detection of Alzheimer’s disease in a mouse model. In the next several years, we plan to commercialize the agent for screening high-risk populations and for monitoring AD treatments with aCdk5-based therapeutics or other AD drugs.

有效治疗550万美国阿尔茨海默病（AD）是迫切需要的， 这种不可逆转的脑部疾病是65岁或65岁以上人群的第三大死因， 痴呆症的原因然而，以前失败的AD药物试验表明，需要将疾病修饰药物 针对AD的早期阶段，以便能够在发生重大损害之前停止疾病。为此 针对早期疾病的治疗干预，检测早期异常变化的可靠方法， 大脑必须开发，突出了对早期检测AD的诊断生物标志物的迫切需要 病理目前AD生物标志物主要用于晚期或AD患者的鉴别诊断。 这些生物标志物的测量不能满足未满足的临床需求，因为它们不能提供有效的诊断 在疾病进展的症状前阶段（症状前AD至轻度认知障碍（MCI）） AD阶段）。一种可能有助于早期发现早期病理和疾病的潜在生物标志物 可能发展为AD的高危人群的进展是异常的细胞周期蛋白依赖性激酶5 （aCdk 5），其在神经毒性应激条件下产生。以前的研究表明，诱导 aCdk 5活性的降低发生在AD病理学之前。Aestas的诊断性神经影像学候选产品针对疾病- 特异性aCdk 5，而不干扰正常功能。aCdk 5被认为是一个“统一的上游”事件， AD病理学的发展。Aestas Pharma将开发一种aCdk 5 PET成像剂AP-251-X，作为第一种 类非侵入性生物标志物检测试剂，用于AD病理的早期检测。该诊断 这种方法有可能促进比现有生物标志物更早地检测AD病理， 与基于aCdk 5的治疗剂或其他候选药物一起用作诊断成像剂， 目标参与或疗效的治疗和监测结果。AP-251-X连接放射性示踪剂， 神经成像与NIH独家许可的小的、高度特异性的aCdk 5抑制肽（AP-PEP 31）。目的 1是开发适合作为诊断显像剂的放射性配体。我们将把这些化合物应用于 PET神经成像在雄性和雌性AD模型小鼠脑中用于早期病理检测。目标二是 在AD模型中测试铅放射性配体作为测量AD治疗结果的工具的可行性。我们将 用aCdk 5阻断剂药物和我们的放射性配体治疗有症状和无症状的AD小鼠， 确定AD样病理的逆转。成功完成SBIR I期研究将使Aestas 制药公司开发了一种aCdk 5选择性诊断方法，用于在小鼠模型中早期检测阿尔茨海默病。 在接下来的几年里，我们计划将该试剂商业化，用于筛查高危人群， 监测用基于aCdk 5的治疗剂或其它AD药物的AD治疗。