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.

摘要 微泡（MB）增强超声溶栓（SL）治疗 急性ST段抬高型心肌梗死（STEMI）、外周动脉闭塞（PAO）和缺血性卒中中的血管闭塞。 然而，没有批准用于这些适应症的甲基溴。血栓是多孔结构， 红细胞纤维蛋白和血小板MB是微米尺寸的结构，可能太大而不能有效渗透 血栓通过血栓切除术、机械破裂和/或生化方法清除闭塞性血栓的努力 已经证明了溶解的功效;然而，这些是耗时的，在改善溶解方面显示出混合的结果。 临床结果，并伴有出血并发症的重大风险。努力提高 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（US）显示 破坏血栓和MB可以在较低能量下局部放大和加速US增强的血栓溶解 水平使用MB的一个警告源于它们的尺寸（1-3微米），这可能限制它们进入内部 MVO和PAO的微血栓更小的声学活性材料，包括相变 纳米液滴（ND，~100-200 nm）应更容易穿透血栓，以增加超声溶栓 疗效和临床疗效。微血管治疗（MVT）已经开发出一种安全，更稳定的脂质- 与Definity®相比，基于MB（MVT-100）的MB不太可能诱发类过敏反应，并且正在开发中 MVT-100通过505（B）（2）途径。此外，MVT随后从MVT-100制备ND（专利，US 9，427，410 B2;本文称为MVT-101）和具有对纤维蛋白具有高亲和力的肽配体的缀合ND （FTND）。纤维蛋白凝块的电子显微镜显示FTND渗透凝块>非靶向ND >> FTMB>MB。 在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体外模型中显示，纤维蛋白微 超声破坏凝块，ND >> MB。最后，我们的国际合作调查员能够在最近的一次 SL治疗急性PAO的临床研究，与标准治疗相比，Depletion ® + US缩短了再灌注时间 裂解治疗沿着。在这个R33催化剂计划中，我们的联合小组建议制定和表征 纤维蛋白靶向MB（FTMB）和ND（FTND），并评估其在体内破坏微血管的有效性 血栓在反映急性心肌梗死和PAO期间MVO的生物学相关模型中的作用。后 为了生产生物缀合物和FTND/FTMB，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激活时实现血栓上级溶解， 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 进行可行性研究，如果成功，将支持进一步的临床前研究。 用于PAO或MVO治疗适应症的ND开发和IND支持研究。