Ultrasound-mediated thrombolysis for MVO and PAO treatment.

用于 MVO 和 PAO 治疗的超声介导溶栓。

• 批准号: 10447822
• 负责人: Emmanuelle Joelle Meuillet
• 金额: $ 35.02万
• 依托单位: MICROVASCULAR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447822
• 关键词: Acoustics; Acute; Acute myocardial infarction; Affinity; Animal Model; Back Pain; Binding; Biochemical; Blood Platelets; Blood Vessels; Caliber; Cell Nucleus; Charge; Clinical; Clinical Research; Coagulation Process; Consumption; Contrast Media; Coronary; Data; Definity; Detection; Development; Diagnostic; Effectiveness; Electron Microscopy; Electrostatics; Excipients; Excision; Exploratory/Developmental Grants Phase II; FDA approved; Feasibility Studies; Fibrin; Formulation; Gas Chromatography; Gases; Generations; Goals; Grant; Hemorrhage; Hindlimb; In Vitro; International; Ischemic Stroke; Laboratories; Legal patent; Ligands; Lipids; Lytic; Measurement; Mechanics; Mediating; Microbubbles; Modeling; Molecular Target; Outcome; Particle Size; Pathway interactions; Peptides; Peripheral; Pharmacologic Substance; Physical condensation; Physiologic pulse; Process; Production; Progress Reports; Publishing; Raman Spectrum Analysis; Rattus; Reaction; Refrigeration; Reperfusion Therapy; Research Personnel; Risk; Safety; Site; Spottings; Structure; System; Temperature; Testing; Therapeutic; Thrombectomy; Thrombus; Time; Transmission Electron Microscopy; Ultrasonography; Universities; artery occlusion; base; clinical development; clinical efficacy; design; efficacy testing; efficacy validation; improved; in vitro Model; in vivo; in vivo Model; indexing; molecular imaging; nanoDroplet; nanosized; novel; phase change; porcine model; preclinical development; pressure; product development; programs; research clinical testing; side effect; stem; thrombolysis; ultrasound

ABSTRACT Encouraging results have been obtained with microbubble (MB) enhanced sonothrombolysis (SL) to treat vascular occlusions in acute ST elevation MI (STEMI), peripheral arterial occlusions (PAO) and ischemic stroke. However, there is no approved MB for these indications. Thrombi are porous structures composed variably of RBC’s, fibrin and platelets. MB are micron sized structures and probably too large to effectively permeate thrombi. Efforts to remove occlusive thrombi via thrombectomy, mechanical disruption, and/or biochemical dissolution have demonstrated efficacy; however, these are time consuming, show mixed results in improving clinical outcomes, and are accompanied by substantial risk of hemorrhagic complications. Efforts to enhance the safety and efficacy of thrombus removal have high potential clinical impact. Ultrasound (US) has been shown to disrupt thrombi and MB can locally amplify and accelerate US-enhanced thrombolysis at a lower energy level. A caveat to the use of MB stems from their size (1-3 microns), which may limit their access to the interior of the microthrombi responsible for MVO and PAO. Smaller acoustically active materials, including phase change nanodroplets (ND, ~100-200 nm), should more easily penetrate thrombus to increase sonothrombolytic efficiency and clinical efficacy. Microvascular Therapeutics (MVT) has developed a safe and more stable lipid- based MB (MVT-100) less likely to induce anaphylactoid reactions as compared to Definity® and is developing MVT-100 via the 505(b)(2) pathway. Moreover, MVT has subsequently made ND from MVT-100 (Patent, US 9,427,410B2; herein referred as MVT-101) and conjugated ND with a peptide ligand with high affinity for fibrin (FTND). Electron microscopy of fibrin clots shows that FTND permeate clot > non-targeted ND >> FTMB>MB. Preliminary studies performed in our laboratory as well as by our collaborators at the University of Pittsburgh Center for Ultrasound Molecular Imaging and Therapeutics in an in vitro model of MVO show that fibrin micro- clots are disrupted by US with ND >> MB. Finally, our international co-Investigator was able to show in a recent clinical study of SL in acute PAO that Definity® plus US shortened the time to reperfusion compared to standard lytic therapy along. In this R33 Catalyze Program, our combined groups propose to formulate and characterize fibrin targeted MB (FTMB) and ND (FTND) and evaluate their effectiveness in vivo in disrupting the microvascular thrombi in biologically relevant models reflective of MVO during acute myocardial infarction and PAO. After production of bioconjugate and FTND/FTMB, we will evaluate their binding to the fibrin target. We hypothesize that FTND will improve fibrin clot detection and achieve superior dissolution of thrombi upon US activation as compared to MB and FTMB. The overall goal of this program is to obtain in vivo results in both animal models for the usage of FTNDs and perform feasibility studies which will, if successful, support further preclinical development and IND-enabling studies of ND for either PAO or MVO therapeutic indication.

抽象的 通过微泡 (MB) 增强声溶栓 (SL) 治疗已获得令人鼓舞的结果 急性 ST 段抬高型心肌梗死 (STEMI)、外周动脉闭塞 (PAO) 和缺血性中风中的血管闭塞。 然而，目前还没有批准用于这些适应症的 MB。血栓是多孔结构，由不同成分组成 红细胞、纤维蛋白和血小板。 MB 是微米大小的结构，可能太大而无法有效渗透 血栓。通过血栓切除术、机械破坏和/或生化清除闭塞血栓 已证明溶解效果；然而，这些都是耗时的，并且在改进方面显示出好坏参半的结果 临床结果，并伴有出血并发症的巨大风险。努力提升 血栓清除的安全性和有效性具有很高的潜在临床影响。超声波（美国）已显示 破坏血栓，MB 可以在较低能量下局部放大和加速超声增强血栓溶解 等级。使用 MB 的一个警告源于它们的尺寸（1-3 微米），这可能会限制它们进入内部 负责 MVO 和 PAO 的微血栓。较小的声学活性材料，包括相变 纳米液滴（ND，〜100-200 nm），应该更容易穿透血栓以增加超声溶栓作用 效率和临床疗效。微血管疗法（MVT）开发了一种安全且更稳定的脂质- 与 Definity® 相比，基于 MB (MVT-100) 的过敏反应可能性较小，并且正在开发中 MVT-100 通过 505(b)(2) 途径。此外，MVT随后以MVT-100（专利，美国 9,427,410B2；本文称为 MVT-101) 并将 ND 与对纤维蛋白具有高亲和力的肽配体缀合 （FTND）。纤维蛋白凝块电镜显示 FTND 渗透凝块 > 非靶向 ND >> FTMB > MB。 我们的实验室以及匹兹堡大学的合作者进行的初步研究 超声分子成像和治疗中心在 MVO 体外模型中表明，纤维蛋白微 血栓被 US 破坏，ND >> MB。最后，我们的国际联合研究员在最近的一项研究中展示了 SL 治疗急性 PAO 的临床研究显示 Definity® plus US 与标准相比缩短了再灌注时间 沿溶解疗法。在这个 R33 催化计划中，我们的联合小组建议制定并表征 纤维蛋白靶向 MB (FTMB) 和 ND (FTND) 并评估它们在体内破坏微血管的有效性 反映急性心肌梗死和 PAO 期间 MVO 的生物学相关模型中的血栓。后 在生物缀合物和 FTND/FTMB 的生产中，我们将评估它们与纤维蛋白靶标的结合。我们假设 FTND 将改善纤维蛋白凝块检测并在 US 激活后实现血栓的卓越溶解 与 MB 和 FTMB 相比。该计划的总体目标是在两种动物模型中获得体内结果 FTND 的使用并进行可行性研究，如果成功，将支持进一步的临床前研究 针对 PAO 或 MVO 治疗适应症的 ND 开发和 IND 启用研究。