A novel approach to delivering therapeutics in heart transplantation

心脏移植治疗的新方法

• 批准号: 10213826
• 负责人: Reza Abdi
• 金额: $ 69.25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213826
• 关键词: Alloantigen; Allograft Tolerance; Allografting; Antigens; Apoptosis; Binding; Biodistribution; Biological Assay; Biology; CD3 Antigens; Calcineurin inhibitor; Cardiac; Cardiovascular system; Cells; Chronic; Clinical; Data; Development; Diabetes Mellitus; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug usage; Endothelium; Engineering; Equilibrium; Failure; Formulation; Future; Generations; Goals; Graft Rejection; Heart; Heart Diseases; Heart Transplantation; High Endothelial Venule; Home; Hypertension; Image; Immune; Immunomodulators; Impairment; Inflammatory; Inflammatory Response; Injury; Kidney; Kinetics; L-Selectin; Life; Lymphatic; Lymphocyte; Lymphoid Tissue; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medicine; Metabolic syndrome; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nano delivery; Nanotechnology; Organ; Organ Transplantation; Outcome; Pathogenesis; Pathogenicity; Patients; Peripheral; Play; Polymers; Property; Regulatory T-Lymphocyte; Risk; Role; Savings; Shapes; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface; System; Systemic infection; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Transplant Recipients; Transplantation; absorption; allograft rejection; anergy; clinical efficacy; controlled release; draining lymph node; drug efficacy; drug mechanism; effector T cell; experimental study; heart allograft; imaging study; improved; in vivo; inflammatory milieu; innovation; insight; intradermal injection; lymph node microenvironment; lymph nodes; lymphocyte trafficking; nanocarrier; nanomedicine; nanoparticle; novel strategies; novel therapeutic intervention; particle; post-transplant; prevent; response; side effect; sound; success; sugar; systemic toxicity; targeted delivery; trafficking; transplant model; virtual

Abstract Cardiac transplantation has become a life-saving strategy for patients with irreversible heart disease. While the development of immunomodulatory drugs (IMD) has played a pivotal role in the success of heart transplantation, nonetheless, there is a substantial unmet need to improve the long-term outcomes of heart transplantation. A large number of cardiac transplant recipients lose their heart transplants due to chronic microvascular injuries. Furthermore, they are also at substantial risk for losing their native organs (such as the kidneys) due to the microvascular toxicities. IMD contribute both directly to these microvascular toxicities by mediating endothelial injuries, and indirectly by playing a pathogenic role in the development of diabetes, the metabolic syndrome and hypertension post-cardiac transplantation. Other serious side effects of IMD include systemic infection and post-transplant malignancy. Therefore, there is a significant unmet need for the development of novel strategies which increase the efficacy and reduce the toxicity of IMD. This proposal seeks to establish an innovative nanodelivery system of IMD in heart transplantation. Pursuing our preliminary data, we will test the hypothesis that targeted delivery of IMD to the draining lymph nodes (DLN) and heart allografts increases the efficacy of IMD, thereby significantly reducing their systemic dosing. The latter should result in reduced systemic toxicity as well. The scientific premise of this proposal is soundly supported by the wealth of information demonstrating that lymphoid tissue are the critical loci for the formation of alloreactive T cells, which eventually home to cardiac allografts and cause cardiac rejection. The field of nanotechnology has created unprecedented opportunities to lay the groundwork for transformative approaches to change the landscape of drug delivery. However, the application of nanomedicine to heart transplantation remains to be developed. Over the past several years, we have developed the first class of nanocarriers for the delivery of IMD to DLN and heart transplants with significant clinical efficacy. These data significantly support the feasibility of the proposed studies. In Aim 1, we plan to characterize and further improve the delivery of IMD to the DLN to further promote heart allograft survival. The proposed studies will employ murine heart transplant models, established functional assays and sophisticated imaging studies to better understand the biodistribution of IMD and their nanocarriers. In Aim 2, we will study the underlying mechanisms by which delivering IMD to the DLN controls the balance of alloreactive T cells and regulatory T cells. In Aim 3, we will capitalize on the unique setting of transplantation where we can deliver IMD directly to heart organs prior to transplantation. These innovative and clinically feasible approaches enable for the first-time better control of the organ’s inflammatory milieu which significantly perpetuate chronic rejection. We believe these studies have the potential to yield paradigm-shifting results enabling the development of transformative and innovative approaches to improve heart transplantation outcomes. !

摘要 心脏移植已成为不可逆心脏病患者的救命之策。 虽然免疫调节药物（IMD）的发展在心脏的成功中发挥了关键作用， 尽管如此，尽管进行了心脏移植，但仍存在大量未满足的需求来改善心脏移植的长期结果。 移植大量的心脏移植受者由于慢性心脏病而失去了他们的心脏移植。 微血管损伤此外，他们还面临着失去原生器官的巨大风险（例如， 肾），由于微血管毒性。IMD直接导致这些微血管毒性， 介导内皮损伤，并间接地在糖尿病的发展中发挥致病作用， 心脏移植后代谢综合征和高血压。IMD的其他严重副作用包括 全身感染和移植后恶性肿瘤。因此，存在显著的未满足的需求， 开发新的策略，提高IMD的疗效并降低其毒性。这项建议 旨在建立心脏移植中IMD的创新纳米递送系统。根据我们初步的 数据，我们将测试IMD靶向递送至引流淋巴结（DLN）和心脏的假设 同种异体移植物增加IMD的功效，从而显著降低其全身剂量。后者应 也导致全身毒性降低。这一建议的科学前提得到了 大量的信息表明淋巴组织是同种异体反应性T细胞形成的关键位点， 这些细胞最终回到心脏移植物中并引起心脏排斥反应。纳米技术领域 创造了前所未有的机会，为采取变革性办法改变 药物输送的景观。然而，纳米医学在心脏移植中的应用仍有待进一步研究。 开发在过去的几年里，我们已经开发出第一类纳米载体，用于递送 IMD到DLN和心脏移植具有显著的临床疗效。这些数据有力地支持了 建议研究的可行性。在目标1中，我们计划描述并进一步改进IMD的交付 以进一步促进心脏移植存活。拟议的研究将采用小鼠心脏移植 模型，建立功能测定和复杂的成像研究，以更好地了解 IMD及其纳米载体的生物分布。在目标2中，我们将研究 将IMD递送至DLN控制同种异体反应性T细胞和调节性T细胞的平衡。在目标3中，我们 利用移植的独特环境，我们可以在移植前将IMD直接输送到心脏器官， 移植这些创新和临床可行的方法首次能够更好地控制 器官的炎症环境会使慢性排斥反应持续存在。我们相信这些研究 产生范式转变结果的潜力，从而能够发展变革性和创新性的 改善心脏移植结果的方法。 !