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)治疗取得了令人鼓舞的结果 急性ST段抬高心肌梗死(STEMI)、外周动脉闭塞(PAO)和缺血性卒中的血管闭塞。 然而，没有批准的甲基溴用于这些适应症。血栓是由不同成分组成的多孔结构 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、机械破碎术和/或生化手段清除闭塞血栓的努力 溶解已经证明是有效的；然而，这些是耗时的，在改善方面表现出好坏参半的结果 临床转归，并伴随着出血并发症的巨大风险。努力加强 血栓清除的安全性和有效性具有很高的临床潜在影响。超声波(美国)已显示 破坏血栓和MB可局部放大并以较低能量加速US增强的溶栓 水平。甲基溴的使用需要注意的是其大小(1-3微米)，这可能会限制它们进入室内 导致MVO和PAO的微血栓。较小的声学活性材料，包括相变 纳米微滴(ND，~100-200 nm)，应更容易穿透血栓，提高声学溶栓效果 有效率和临床疗效。微血管治疗学(MVT)已经开发出一种安全和更稳定的脂质- 与Definity®相比，基于MB(MVT-100)的MB(MVT-100)引起类过敏反应的可能性较小，正在开发中 MVT-100通过505(B)(2)途径。此外，MVT随后从MVT-100制造ND(专利，美国 9,427,410B2；这里称为MVT-101)和与纤维蛋白具有高亲和力的多肽配体结合的ND (FTND)。纤维蛋白凝块的电子显微镜显示FTND渗透到非靶向的纤维蛋白凝块中。 在我们的实验室以及我们在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，纤维蛋白微球 美国用ND&>；&>MB破坏血块。最后，我们的国际合作调查员能够在最近的一次 Definity®加US缩短再通时间的SL在急性PAO中的临床研究 继续进行溶栓治疗。在这个R33催化计划中，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)及其体内破坏微血管的效果评价 反映急性心肌梗死期间MVO和PAO的生物学相关模型中的血栓。之后 生物偶联物和FTND/FTMB的生产，我们将评估它们与纤维蛋白靶标的结合。我们假设 FTND将改进纤维蛋白凝块的检测，并在US激活时实现卓越的血栓溶解，因为 与甲基溴和FTMB相比。该计划的总体目标是在两种动物模型中获得活体结果 使用FTND，并进行可行性研究，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的开发和使能研究。