Development of a novel ophthalmic probe for cerebral amyloid angiopathy

开发用于脑淀粉样血管病的新型眼科探针

• 批准号: 9907957
• 负责人: Stella Sarraf
• 金额: $ 49.03万
• 依托单位: AMYDIS DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907957
• 关键词: Address; Advanced Development; Age; Age-associated memory impairment; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Arteries; Autopsy; Binding; Biological Markers; Biopsy; Blood Vessels; Brain; Brain hemorrhage; Canis familiaris; Caring; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; Chemistry; Clinic; Clinical; Clinical Research; Clinical Trials; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dose; Drug Kinetics; Early Diagnosis; Elderly; Eye; Fluorescence; Fluorescent Probes; Formulation; Goals; Hand; Histopathology; Human; Imaging Techniques; In Vitro; Investigational Drugs; Lead; Legal patent; Libraries; Magnetic Resonance Imaging; Metabolism; Mission; Monitor; Neuraxis; Neurologist; One-Step dentin bonding system; Outcome; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Physicians; Preparation; Procedures; Process; Prodrugs; Property; Rattus; Reporting; Research; Retina; Retinal; Risk; Safety; Specialist; Stroke; Symptoms; Technology; Testing; Tissues; Toxic effect; Transgenic Mice; Validation; Work; base; brain tissue; chemical synthesis; clinical candidate; design; diagnosis standard; experimental study; genotoxicity; healthy volunteer; improved; in vivo; innovation; inorganic phosphate; meetings; metabolic abnormality assessment; mouse model; novel; off-patent; preclinical study; small molecule; standard care; standard of care; stroke risk; 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 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 ante-mortem diagnostic is needed that can reliably identify CAA at the early, asymptomatic stages, enabling a correct diagnosis to avoid medications contraindicated in the disease. Furthermore, a useful and affordable outcome marker is needed for clinical trials focused on therapies for CAA that could stop or reverse 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. Several amyloid forming peptides can lead to CAA, among them, amyloid beta (1-40), Aβ40, is by far the most prevalent form. Amydis’ probes have demonstrated significant fluorescence enhancement in vitro with synthetically aggregated Aβ40, the ability to detect retinal amyloid deposits in vivo in transgenic mouse models, and detection of amyloid deposits ex vivo with human brain tissue from CAA patients. We have selected our lead clinical candidate, AMDX- 2011P, based on properties amenable for commercial development. With this proposal we aim to 1) develop a chemical synthesis and formulation of AMDX-2011P in preparation for clinical trials, 2) complete preclinical studies to assess the metabolism, pharmacokinetics and toxicity of AMDX- 2011P and 3) complete investigational new drug (IND) enabling studies to file an IND with the FDA. Completion of these aims will advance the development of our in vivo ocular diagnostic test into human clinical trials, getting us one step closer to our mission of providing an ante-mortem, simple and affordable CAA diagnostic.

项目概要 脑淀粉样血管病（CAA）是老年人中常见的神经病理学发现 成人的特征是大脑血管壁中沉积有β淀粉样蛋白（Aβ）。 是自发性脑出血的主要原因，也是年龄增长的重要因素 相关的认知能力下降常常被医生忽视。 与中风相似，并且可能会更加复杂，因为超过 80% 的阿尔茨海默病患者中都存在 CAA 可能的 CAA 的标准诊断涉及昂贵的成像技术。 诊断 CAA 的唯一确定方法是尸检。 需要进行生前诊断，以便能够在早期可靠地识别 CAA。 无症状阶段，能够做出正确的诊断，避免使用禁忌药物 此外，针对重点临床试验需要一种有用且负担得起的结果标记物。 Amydis 旨在开发能够阻止或逆转疾病进展的 CAA 疗法。 通过识别眼睛中的 A 作为大脑的窗口，尽早解决这些未满足的需求 CAA的检测。 几种淀粉样蛋白形成肽可导致 CAA，其中，淀粉样蛋白 β (1-40)、Aβ40、 是迄今为止最普遍的形式，Amydis 的探针已显示出显着的荧光。 使用合成聚集的 Aβ40 增强体外检测视网膜淀粉样蛋白的能力 转基因小鼠模型中的体内沉积物，以及离体淀粉样沉积物的检测 我们选择了我们的主要临床候选药物 AMDX-。 2011P，基于适合商业开发的房产，我们的目标是： 1) 开发AMDX-2011P的化学合成和配方，为临床试验做准备， 2) 完成临床前研究以评估AMDX-的代谢、药代动力学和毒性 2011P 和 3) 完成研究性新药 (IND)，使研究能够向 FDA 提交 IND FDA 这些目标的完成将推动我们体内眼部诊断测试的发展。 进入人体临床试验，使我们更接近提供死前检验的使命， 简单且经济实惠的 CAA 诊断。