Development of an ophthalmic diagnostic probe for cerebral amyloid angiopathy in patients

脑淀粉样血管病眼科诊断探针的研制

• 批准号: 10253366
• 负责人: Stella Sarraf
• 金额: $ 159.09万
• 依托单位: AMYDIS DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253366
• 关键词: Address; Advanced Development; Age; Age-associated memory impairment; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Arteries; Autopsy; Award; Binding; Biological Markers; Biopsy; Blood Vessels; Boston; Brain; Brain hemorrhage; Capital; Caring; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; Clinical; Clinical Trials; Collaborations; Complement; Data; Databases; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dose; Drug Kinetics; Drug Prescriptions; Early Diagnosis; Elderly; Equipment; Eye; Fluorescence; Fluorescent Probes; Formulation; Generations; Goals; Guidelines; Hemorrhage; Histopathology; Human; Imaging Techniques; In Vitro; Individual; Intravenous; Iowa; Kilogram; Laboratories; Lead; Magnetic Resonance Imaging; Methods; Mission; Ophthalmologist; Outcome; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Physicians; Plasma; Procedures; Production; Property; Reporting; Research; Retina; Risk; Safety; Secure; Series; Specialist; Stroke; Symptoms; Testing; Tissues; Toxicology; Transgenic Mice; Universities; Work; abeta deposition; authority; cohort; commercialization; cost; cost effective; crystallinity; design; diagnosis standard; disease diagnosis; fluorescence imaging; high risk; improved; in vivo; instrument; meetings; mouse model; novel; pre-clinical; preclinical study; programs; response; retinal imaging; scale up; screening; small molecule; stability testing; standard care; stroke risk; stroke-like outcome; tool

Project Summary Cerebral amyloid angiopathy (CAA) is a common neuropathological finding among older adults and is characterized by amyloid beta (Aβ) deposits in blood vessel walls of the brain. CAA is a major cause of spontaneous intracerebral hemorrhage and is an important contributor to age related cognitive decline. Diagnosis is often missed by physicians as the presenting symptoms are similar to a stroke and can be further complicated as CAA is found in over 80% of Alzheimer's disease patients. Standard diagnosis of probable CAA involves expensive imaging techniques and an invasive brain biopsy. The only definitive way to diagnose CAA is through post-mortem analysis. An antemortem diagnostic is needed that can reliably identify CAA at the early, asymptomatic stages, enabling a correct diagnosis to avoid medications contraindicated in the disease, which can increase the individual's stroke risk. Furthermore, a useful and affordable outcome marker is needed for clinical trials focused on therapies for CAA that could stop or reverse the progression of the disease. Amydis aims to address these unmet needs by identifying A in the eye, as a window to the brain, for early detection of CAA. Amydis is meeting this need with the development of a novel retinal diagnostic probe. Our novel retinal diagnostic probe, AMDX-2011P, has fluorescent properties amenable for use with standard retinal imaging equipment found in the ophthalmologists' office and fluoresces at a wavelength suitable for use with conventional instruments, it penetrates the retina when administered systemically at significant concentrations, is non-toxic in preclinical animal models, and has crystalline properties that allow for consistent large-scale manufacturing. In this proposal, Amydis will manufacture AMDX-2011P under GMP guidelines, formulate AMDX-2011P for i.v. delivery, test stability, and then undertake a phase 1 clinical trial with single ascending doses in healthy subjects (N=24) and then test the optimal dose in a small cohort of CAA patients (N=5). Completion of these aims will advance the development of our in vivo ocular diagnostic test, getting us one step closer to our mission of providing an antemortem, simple, and affordable CAA diagnostic.

项目摘要 脑淀粉样血管病（CAA）是老年人中常见的神经病理学发现， 特征为淀粉样蛋白β（Aβ）沉积在脑血管壁上。CAA是导致 自发性脑内出血，是与年龄相关的认知能力下降的重要原因。 诊断往往是错过了医生的表现症状类似中风，可以进一步 CAA在80%以上的阿尔茨海默病患者中被发现。可能CAA的标准诊断 涉及昂贵的成像技术和侵入性脑活检诊断CAA的唯一明确方法 就是通过验尸分析需要一种死前诊断，可以在早期可靠地识别CAA， 无症状阶段，使正确的诊断，以避免药物禁忌的疾病， 会增加患者中风的风险此外，还需要一个有用和负担得起的成果标志， 临床试验集中在CAA的治疗上，可以阻止或逆转疾病的进展。阿米迪斯 旨在通过识别眼睛中的A β来解决这些未满足的需求，作为大脑的窗口，以便早期发现 CAA。Amydis正在开发一种新型视网膜诊断探针来满足这一需求。我们的新型视网膜 诊断探针AMDX-2011 P具有荧光特性，适合用于标准视网膜成像 在眼科医生的办公室中发现的设备，并且在适合于与常规的眼科医生一起使用的波长下发出荧光。 仪器，当以显著浓度全身给药时，它穿透视网膜，在 临床前动物模型，并具有允许一致的大规模生产的结晶性质。在 根据该提案，Amydis将根据GMP指导原则生产AMDX-2011 P，配制AMDX-2011 P用于i. v. 交付，测试稳定性，然后在健康受试者中进行单次剂量递增的I期临床试验 （N=24），然后在CAA患者的小队列（N=5）中测试最佳剂量。实现这些目标将 推进我们体内眼部诊断测试的发展，使我们更接近我们的使命， 提供了一种死前、简单且经济实惠的CAA诊断方法。