Phase II: Percutaneous deliverable biomaterial for treating myocardial infarction

描述(由申请人提供)：心肌梗塞(MI)后的心力衰竭仍然是西方世界的头号杀手。在美国，估计每年的心肌梗死(MI)发病率为745,000新发和410,000例复发。由于终末期心力衰竭只能通过心脏移植或左心室(LV)辅助装置来治疗，因此迫切需要开发新的治疗方法，而目前的药物治疗方案不能充分防止MI后负向左室重构。作为全心脏移植的替代方案，细胞心肌成形术或细胞移植已经被探索用于 治疗心肌梗死和心力衰竭；然而，最近一种细胞生物材料在提供类似的功能益处方面显示出巨大的希望，而不会出现与细胞输送相关的并发症。生物材料产品的主要优势是现成的，制造成本相对较低。然而，现有的材料是有限的，因为没有一种材料是专门为心肌设计的，也没有一种材料模仿他们打算取代的心肌梗死后降解的细胞外基质(ECM)。这些材料的问题是：1)它们不能通过当前的导管技术提供，和/或2)它们缺乏复杂的、心肌特异性的ECM信号，这有助于修复。用于Ventrix产品的材料是第一个可以通过导管输送的心肌特定材料，以促进心肌梗塞后环境中的修复。这种材料在室温下是液体，注入心肌后形成多孔的纤维支架。我们已经证明，在大鼠心肌梗死模型中，它促进细胞内流，增加存活心肌细胞的面积，并保留左室构型和心功能，并可在猪模型中通过经皮经心内膜途径传递。在我们的第一阶段SBIR中，我们证明了VentriGelTM在猪MI模型中增加了心肌，改善了心功能，并防止了基于导管的输送后的负向左室重构。第二阶段提出的研究是启动在患者身上研究VentriGelTM的最后步骤的一部分，也是将一种生物材料产品推向市场的关键一步，该产品将与目前的MI药物市场互补或基本平行。在第二阶段，我们将实现以下两个具体目标，以实现我们的目标：1)证明交付VentriGel“后心肌梗死后的心功能改善和负向左心室重构，并在猪急性心肌梗死模型中确定其最佳容量和递送时间窗；2)通过IND提交FDA所需的毒理学研究，评估VentriGel的安全性。拟议项目的目标是完成VentriGelTM的关键临床前研究，以便转化为临床。这将是首个用于治疗数百万心肌梗死患者的导管可释放再生生物材料产品。

DESCRIPTION (provided by applicant): Heart failure following a myocardial infarction (MI) continues to remain a leading killer in the western world. In the United States, the estimated annual incidence of myocardial infarction (MI) is 745,000 new and 410,000 recurrent episodes. There is a critical need to develop new therapies since end-stage heart failure is only treated through heart transplantation or left ventricular (LV) assist devices, and current pharmaceutical regimens do not adequately prevent post-MI negative LV remodeling. As an alternative to total heart transplantation, cellular cardiomyoplasty, or cell transplantation, has been explored for the treatment of MI and heart failure; however, more recently a cellular biomaterials have shown great promise in providing similar functional benefit without the complications associated with cell delivery. Biomaterial products have the key advantages of being off-the-shelf available and relatively inexpensive to manufacture. Existing materials have however been limited since none have been specifically designed for the myocardium, and none mimic the degraded post-MI extracellular matrix (ECM) they are intended to replace. The materials suffer from 1) their inability to be delivered via current catheter technology, and/or 2) their lack of complex, myocardial specific ECM cues, which promote repair. The material used for the Ventrix product is the first example of a myocardial-specific material that can be delivered via catheter to promote repair in the post-MI environment. This material is liquid at room temperature and forms a porous and fibrous scaffold upon injection into the myocardium. We have shown that it promotes cell influx, increases areas of surviving cardiomyocytes, and preserves LV geometry and cardiac function in a rat MI model, and can be delivered through a percutaneous transendocardial approach in a porcine model. In our Phase I SBIR, we demonstrated that VentriGelTM increased cardiac muscle, improved cardiac function, and prevented negative LV remodeling following catheter based delivery in a porcine MI model. The studies proposed in Phase II are part of the final steps to initiate studying VentriGelTM in patients, and a key step i bringing a biomaterial product to market, which will be complementary or mostly parallel to the current MI pharmaceutical market. In Phase II, we will achieve the following two specific aims to reach our goals: 1) To demonstrate an improvement in cardiac function and negative LV remodeling following delivery of VentriGel" post-myocardial infarction and to determine its optimal volume and delivery time window in a porcine acute myocardial infarction model and 2) To assess safety of VentriGel" via toxicology studies required for IND submission to the FDA. The objective of the proposed project is to complete the key preclinical studies for VentriGelTM to translate to the clinic. This will be the first catheter deliverable regenerative biomaterial product for treating the millions of patients suffering from MI.