Phase II: Percutaneous deliverable biomaterial for treating myocardial infarction

描述（由申请人提供）：心肌梗死（MI）后的心力衰竭仍然是西方世界的主要杀手。在美国，心肌梗死（MI）的估计年发病率为745，000新发和410，000复发发作。由于终末期心力衰竭仅通过心脏移植或左心室（LV）辅助装置治疗，并且目前的药物方案不足以预防MI后负性LV重塑，因此迫切需要开发新的疗法。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 然而，最近，细胞生物材料在提供类似的功能益处而没有与细胞递送相关的并发症方面显示出很大的前景。生物材料产品的主要优点是现成可用，制造成本相对较低。然而，现有的材料受到限制，因为没有一种材料是专门为心肌设计的，也没有一种材料模拟它们旨在替代的降解的MI后细胞外基质（ECM）。这些材料的缺点是：1）它们不能通过当前的导管技术递送，和/或2）它们缺乏促进修复的复杂的心肌特异性ECM线索。Ventrix产品使用的材料是第一个心肌特异性材料的例子，可以通过导管输送，以促进MI后环境中的修复。这种材料在室温下是液体，并且在注射到心肌中时形成多孔和纤维支架。我们已经表明，它促进细胞流入，增加存活心肌细胞的面积，并保留左心室的几何形状和心脏功能在大鼠心肌梗死模型，并可以通过经皮transendoembolism方法在猪模型。在我们的I期SBIR中，我们证明了VentriGelTM在猪MI模型中基于导管输送后增加了心肌，改善了心脏功能，并防止了负性LV重塑。II期拟议的研究是开始在患者中研究VentriGelTM的最后步骤的一部分，也是将生物材料产品推向市场的关键步骤，这将是对当前MI药物市场的补充或大部分平行。在II期研究中，我们将实现以下两个具体目标以达到我们的目标：1）证明心肌梗死后输送VentriGel后心脏功能和左心室负性重塑的改善，并确定其在猪急性心肌梗死模型中的最佳体积和输送时间窗; 2）通过向FDA提交IND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，以转化为临床。这将是第一个导管输送再生生物材料产品，用于治疗数百万患有心肌梗死的患者。

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.