Development of Fibrin-Specific Nuclear Probe to Reduce LVAD Adverse Events

开发纤维蛋白特异性核探针以减少 LVAD 不良事件

基本信息

  • 批准号:
    9607429
  • 负责人:
  • 金额:
    $ 76.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

Despite the myriad major advances in cardiology, the prognosis for patients with severe, medically refractive heart failure (HF) is exceedingly poor. Approximately 287,000 deaths occur annually in patients with HF who have endured an impaired quality of life often accompanied by significant economic and personal losses due to recurrent hospitalizations. At least 58,000 of these deaths were directly related to severe heart failure. Because the number of available heart donors (~2,200/year) has not increased over the last decade, there is an enormous and expanding gap between medical need for transplant and the woefully low supply of hearts. Today's axial and centrifugal flow left ventricular assist devices (LVAD) have reduced size and power requirements, allowing LVADs to become a therapeutic options as a bridge-to-transplantation (BTT) and increasingly for destination-therapy (DT). Unfortunately the life-saving benefit of LVADs is offset by potential life-threatening complications and costly hospital readmissions for bleeding, infection, and thrombosis. Prophylactic anticoagulation to prevent intra-pump thrombus with warfarin (in addition to an anti-platelet drug) exacerbates inherent bleeding complications induced by the high shear high blood flow conditions of the pumps. Multicenter efforts to reduce anticoagulation guidelines tripled the incidence of pump thrombotic complications. LDH, a nonspecific marker of RBC lysis, is currently used as the best surrogate indicator for pump thrombosis. But, given clinical results to date, LDH is only an insensitive probably late biomarker of LVAD fibrin accumulation. We have innovated and demonstrated a very high avidity nuclear probe prototype, 99mTc-F4A, in vitro, in excised LVADs operated ex vivo, and in rodent models, which sensitively localizes thrombus accumulation in LVADs. In Phase 1 of this Fast-track proposal the effectiveness of 99mTc-F4A will be demonstrated in a large animal model, calves (70kg), using reimplanted human LVADs (70Kg) and a clinical gamma camera. In Phase 2 the analytical, chemical process, and regulatory development and documentation required to transfer the product candidate (FibroScint) to contract research organizations for GMP toll manufacturing, stability testing, and GLP toxicology will be completed. FibroScint is anticipated to refine and individualize LVAD clinical management to reduce bleeding events, thromboembolic complications and pump exchanges.
尽管心脏病学取得了无数重大进展,但严重的,医学上的, 屈光性心力衰竭(HF)非常差。每年约有287,000人死亡, 生活质量受损的HF患者通常伴有显著的 由于反复住院造成的经济和个人损失。其中至少有58,000人死亡, 与严重心力衰竭直接相关由于可用的心脏供体数量(约2,200/年) 在过去的十年里,没有增加,医疗需求之间存在巨大的和不断扩大的差距, 移植和心脏供应少得可怜。 今天的轴向和离心流左心室辅助装置(LVAD)具有减小的尺寸和更小的体积。 功率要求,使LVAD成为治疗选择,作为移植的桥梁 (BTT)并越来越多地用于目的地治疗(DT)。不幸的是,LVAD的救生益处是 但由于潜在的危及生命的并发症和因出血,感染, 和血栓形成。预防性抗凝治疗,以预防华法林泵内血栓(此外 抗血小板药物)加剧了由高剪切力引起的固有出血并发症 泵的血流条件。多中心努力减少抗凝指南, 泵血栓并发症的发生率。LDH是红细胞溶解的非特异性标志物, 作为泵血栓形成的最佳替代指标。但是,考虑到迄今为止的临床结果,LDH只是一种 LVAD纤维蛋白蓄积的不敏感的可能晚期生物标志物。 我们已经创新并展示了一种非常高亲合力的核探针原型,99 mTc-F4 A, 在体外、离体操作的切除LVAD和啮齿动物模型中,可敏感地定位血栓 LVAD中的蓄积。在这个快速通道提案的第一阶段,99 mTc-F4 A的有效性将是 在大型动物模型中证实,小牛(70 kg),使用重新植入的人LVAD(70 kg)和 医用伽马照相机在第2阶段,分析、化学工艺和法规开发, 将候选产品(FibroScint)转移至合同研究所需的文件 将完成GMP生产、稳定性试验和GLP毒理学的组织。 预计FibroScint将完善和个性化LVAD临床管理,以减少 出血事件、血栓栓塞并发症和泵更换。

项目成果

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James Blackledge其他文献

James Blackledge的其他文献

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{{ truncateString('James Blackledge', 18)}}的其他基金

Development and Commercialization of a New Molecularly Targeted Imaging Agent for Multiple Myeloma
新型多发性骨髓瘤分子靶向成像剂的开发和商业化
  • 批准号:
    10885315
  • 财政年份:
    2021
  • 资助金额:
    $ 76.86万
  • 项目类别:
Development of Fibrin-Specific Nuclear Probe to Reduce LVAD Adverse Events
开发纤维蛋白特异性核探针以减少 LVAD 不良事件
  • 批准号:
    9410234
  • 财政年份:
    2017
  • 资助金额:
    $ 76.86万
  • 项目类别:

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