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是一种影响美国大量老年人的疾病，其自然病史导致主动脉壁结构性失效和死亡，AAA仍然代表着对生物治疗的迫切需求。再生治疗包括将干细胞输送到受损的主动脉，这在概念上为主动脉壁基质的重建提供了很好的机会，因此主动脉强度-这种治疗的任何测试都必须在已建立的动脉瘤上进行，以最准确地代表临床上发生的情况。 在这项提案中，我们结合了两个实验室的优势，具有互补的科学能力，并在开发有效的AAA疾病生物疗法方面具有共同的兴趣。这种合作配对的早期产品是发表的“概念证明”证据，即间充质干细胞（MSC）递送到小鼠AAA的壁可以减缓进展。 本R21探索性/开发性研究提案的目的是开发一种临床上可转化的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性辅助将局部干细胞递送至小鼠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，使用水凝胶载体和磁性引导将MSC外膜周围输送到主动脉壁中。该技术将通过在体外和体外测试铁纳米颗粒类型、纤维蛋白水凝胶制剂和干细胞浓度的干部来优化。具体目标2是证明局部MSC递送在已建立的啮齿动物模型中停止并逆转AAA的功能和结构变性。在特定目标1中开发的MSC水凝胶将在允许不同程度的基质变性后应用于弹性蛋白酶诱导的模型AAA的外膜。各种疗法相对于无细胞水凝胶对照对主动脉组织的成功验证将涉及：i）功能评估（包括主动脉直径和生物力学参数）和ii）详细的显微结构和细胞组成评估。 这项工作的预期成果是开发和验证一种新的干细胞输送到AAA的技术。

 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.