Targeted Imaging of Fibrosis in the Left Atrium

左心房纤维化的靶向成像

• 批准号: 10384068
• 负责人: Valerie Humblet
• 金额: $ 76.6万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384068
• 关键词: Targeted; Imaging; Fibrosis; Left; Atrium

Abstract Significance: Atrial fibrosis plays a central role in the development of atrial fibrillation (AF) and heart failure, which are both common conditions in the elderly and associated with significant morbidity and mortality. This proposal addresses an unmet diagnostic need for non-invasive methods to characterize atrial fibrosis through non-invasive molecular imaging of type 1 collagen, the hallmark pathology of atrial fibrosis. Hypothesis: We hypothesize that a collagen-binding gadolinium chelate will localize in fibrotic atrial tissue, thus enabling targeted molecular imaging of atrial fibrosis to be performed with a high degree of accuracy. Preliminary data: The affinity and specificity of Collagen Medical’s proprietary probe CM-101 for type 1 collagen are well established. Our preliminary efficacy data have established that CM-101 can quantify fibrosis burden in a rat bile duct ligation model (BDL) of chronic liver disease. Additionally, CM-101 enhanced differences in T1 and signal intensity in a canine myocardial infarct model were shown to be related to the fibrosis burden in the left ventricle. Here, for the first time, we propose to use the agent to image left atrial fibrosis using a porcine model of atrial fibrillation. Specific Aims: In Phase 1, Specific Aim 1, of this Fast Track proposal we aim to establish that CM-101 specifically accumulates in regions of atrial fibrosis as compared with a non-targeted control and that it can be imaged in vivo with T1 weighted sequences. A porcine model of focal left atrial fibrosis created using radiofrequency ablation catheters will be used. The gating decision criteria for a transition to Phase 2 are based on quantitative assessment of tissue specificity vs. non-targeted control and in vivo imaging. In Phase 2, Specific Aim 2 of the grant, we will demonstrate the ability of CM-101 enhanced MRI to quantify patchy and diffuse left atrial fibrosis in a porcine model of atrial fibrillation and will compare the collagen targeted agent to the current gold standard, late gadolinium enhancement (LGE) using the non-targeted agent (Gd-DOTA). Overall Impact: We anticipate that the targeted and specific nature of CM-101 will produce significantly more accurate data than LGE using non-targeted chelates, the current gold standard. Together, data obtained in these studies will support an IND application and accelerate translation into the clinical realm.

抽象的 意义：心房纤维化在心房颤动 (AF) 和心力衰竭的发展中起着核心作用， 这都是老年人的常见病症，并且与显着的发病率和死亡率相关。 该提案解决了通过非侵入性方法来表征心房纤维化的未满足的诊断需求 1 型胶原的非侵入性分子成像，心房纤维化的标志性病理学假设：我们。 随后，胶原蛋白结合钆螯合物将定位于纤维化心房组织中，从而使 心房纤维化的靶向分子成像的初步数据： Collagen Medical 专有的探针 CM-101 对 1 型胶原蛋白的亲和力和特异性非常好 我们的初步疗效数据表明 CM-101 可以量化大鼠的纤维化负担。 此外，CM-101 增强了慢性肝病的胆管结扎模型 (BDL) 的 T1 和 T1 差异。 犬心肌梗塞模型中的信号强度被证明与左侧纤维化负担有关 在这里，我们首次建议使用该试剂通过猪模型对左心房纤维化进行成像。 房颤的具体目标：在本快速通道提案的第一阶段，具体目标 1，我们旨在建立 与非靶向对照相比，CM-101 专门积聚在心房纤维化区域，并且 可以使用 T1 加权序列对猪的局灶性左心房纤维化模型进行体内成像。 将使用射频消融导管过渡到第 2 阶段的门控决策标准。 基于组织特异性与非靶向对照和体内同相成像的定量评估。 2、资助的具体目标2，我们将展示CM-101增强MRI量化斑片和 在猪心房颤动模型中进行弥漫性左心房纤维化，并将胶原蛋白靶向药物与 当前的黄金标准是使用非靶向剂 (Gd-DOTA) 的晚期钆增强 (LGE)。 总体影响：我们预计 CM-101 的针对性和特定性将产生更多的影响 比 LGE 使用非靶向螯合物（当前的黄金标准）获得的数据更准确。 这些研究将支持 IND 申请并加速向临床领域的转化。