Development of a novel ophthalmic probe for cerebral amyloid angiopathy

项目总结 摘要脑淀粉样血管病(CAA)是老年人常见的神经病理改变。 以大脑血管壁中的淀粉样β蛋白(Aβ)沉积为特征。CAA 是自发性脑出血的主要原因，也是导致年龄增长的重要因素 相关的认知能力下降。内科医生常常将诊断漏诊为主要症状。 类似于中风，并可能进一步复杂化，因为超过80%的阿尔茨海默氏症患者存在CAA 疾病患者。疑似CAA的标准诊断涉及昂贵的成像技术 还有侵入性脑活组织检查。诊断CAA的唯一确定方法是通过尸检 分析。需要能够在早期可靠地识别CAA的事前诊断， 无症状阶段，使正确的诊断，以避免药物禁忌 疾病。此外，临床试验需要一个有用的和负担得起的结果标记物。 关于可以阻止或逆转疾病进展的CAA治疗方法。Amydis的目标是 通过早期识别眼睛中的作为大脑的窗口来解决这些未得到满足的需求 CAA的检测。 几种淀粉样蛋白形成肽可导致冠状动脉再生障碍性贫血，其中淀粉样β蛋白(1-40)，Aβ40， 是目前为止最流行的形式。Amydis的探针已经显示出显著的荧光 合成聚合体Aβ40体外增强检测视网膜淀粉样蛋白的能力 转基因小鼠体内沉积，以及体外检测淀粉样蛋白沉积 CAA患者的人脑组织。我们已经选出了我们的主要临床候选药物AMDX- 2011P，基于适合商业开发的物业。通过这项建议，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)完成研究新药(IND)，使研究能够向 美国食品和药物管理局。这些目标的完成将推动我们体内眼科诊断测试的发展 进入人体临床试验，让我们离提供尸检的使命又近了一步， 简单且经济实惠的CAA诊断。

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.