Outside-In Regenerative Therapy for Abdominal Aortic Aneurysm

 描述(由申请人提供)：很少有疾病比腹主动脉瘤(AAA)更能代表再生细胞治疗的最佳潜在靶点。AAA是一种在美国影响大量老年人的疾病，有自然病史，导致主动脉壁结构性故障和死亡，AAA仍然是生物治疗的迫切需要。将干细胞输送到受损的主动脉的再生疗法在概念上为重建主动脉壁基质提供了一个很好的机会，因此，任何对这种疗法的测试都必须在已建立的动脉瘤上进行，以最准确地反映临床上发生的情况。在这项建议中，我们结合了两个实验室的优势，具有互补的科学能力，并对开发有效的AAA疾病生物疗法具有共同兴趣。这一合作配对的早期成果是发表了“概念证明”证据，证明将间充质干细胞(MSC)运送到小鼠AAA的壁上可以减缓进展。这项R21探索性/发展研究提案的目的是开发一种临床可翻译的MSC输送系统，该系统将导致主动脉基质修复和再生。我们的假设是，通过外膜应用的水凝胶和磁辅助将局部干细胞输送到小鼠AAA将导致壁内细胞植入、基质修复和主动脉壁的机械稳定。为了解决我们的假设，我们将执行以下具体目标：具体目标1是开发和验证一种技术，利用水凝胶载体和磁引导将MSCs运送到主动脉壁周围。这项技术将通过在体外和体外测试一系列铁纳米颗粒类型、纤维蛋白水凝胶配方和干细胞浓度来优化。具体目的2是证明在已建立的啮齿动物模型中，局部MSC传递停止并逆转AAA的功能和结构退化。在允许不同程度的基质退化后，针对特定目标1开发的MSC水凝胶将应用于弹性酶诱导的AAA模型的外膜。对主动脉组织进行各种治疗与无细胞水凝胶对照的成功标准将包括：i)功能评估(包括主动脉直径和生物力学参数)和ii)详细的微结构和细胞组成评估。这项工作的预期结果是为AAA提供干细胞的新技术的开发和概念验证。

 DESCRIPTION (provided by applicant): Few diseases represent the optimal potential target for regenerative cellular therapy more than the abdominal aortic aneurysm (AAA). A disease that affects a large number of elderly in the United States with a natural history that results in structural failure of the aortic wall and death, AAA continues to represent a critical need for biologic therapy. Regenerative therapy consisting of the delivery of stem cells to the damaged aorta presents a conceptually strong opportunity for the reconstitution of the aortic mural matrix and therefore aortic strength - any test of such a therapy must be done on an established aneurysm to most accurately represent what occurs in the clinic. In this proposal, we have combined the strengths of two laboratories with complementary scientific capability, and with a common interest in the development of effective biologic therapies for AAA disease. The early product of this collaborative pairing is published "proof of concept" evidence that mesenchymal stem cell (MSC) delivery to the wall of a murine AAA can slow progression. The purpose of this R21 Exploratory/Developmental Research Proposal is to develop a clinically- translatable MSC delivery system that would result in aortic matrix repair and regeneration. Our hypothesis is that local stem cell delivery to a murine AAA via an adventitially-applied hydrogel and magnetic assistance will result in intramural cell engraftment, matrix repair, and mechanical stabilization of the aortic wall. To address our hypothesis, we will execute the following specific aims: Specific Aim 1 is to develop and validate a technique to deliver MSCs into the aortic wall periadventitially using a hydrogel vehicle and magnetic guidance. The technique will be optimized by testing a cadre of iron nanoparticle types, fibrin hydrogel formulations, and stem cell concentrations both in vitro and in vitro. Specific Aim 2 is to demonstrate that local MSC delivery halts and reverses the functional and structural degeneration of an AAA in an established rodent model. MSC hydrogels developed in Specific Aim 1 will be applied to the adventitia of an elastase-induced model AAA after allowing for varying degrees of matrix degeneration. Metrics for success of the various therapies versus cell-free hydrogel controls on aortic tissue will involve: i) functional assessment (including aortic diameter and biomechanical parameters) and ii) detailed microstructural and cellular composition assessment. The expected outcome of this work is the development and proof-of-concept of a new technology for stem cell delivery to AAA.