A novel approach to delivering therapeutics in heart transplantation

心脏移植治疗的新方法

• 批准号: 10449346
• 负责人: Reza Abdi
• 金额: $ 56.27万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449346
• 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; Immune; Immunomodulators; Impairment; Inflammatory; Inflammatory Response; Injury; Kidney; Kinetics; L-Selectin; Life; Lymphatic; Lymphocyte; Lymphoid Tissue; Malignant Neoplasms; 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; mass spectrometric imaging; 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 心脏移植已经成为不可逆转心脏病患者的一种挽救生命的策略。 而免疫调节药物(IMD)的发展对心脏的成功起到了关键作用 然而，在改善心脏移植的长期结果方面，仍有大量未得到满足的需求。 移植。大量心脏移植受者因慢性疾病而失去心脏移植 微血管损伤。此外，他们还面临失去固有器官的巨大风险(如 肾脏)由于微血管毒性。IMD通过以下途径直接导致这些微血管毒性 介导内皮细胞损伤，并间接通过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 全身感染和移植后的恶性肿瘤。因此，有一个重大的未满足的需求 开发新的策略，提高IMD的疗效并降低其毒性。这项建议 旨在建立一种创新的IMD纳米给药系统用于心脏移植。正在进行我们的初步调查 数据，我们将检验IMD靶向向引流淋巴结(DLN)和心脏递送的假设 同种异体移植可提高IMD的疗效，从而显著减少其全身剂量。后者应该 也降低了全身毒性。这项建议的科学前提得到了 大量信息表明淋巴组织是同种异体反应性T细胞形成的关键部位 细胞，这些细胞最终是同种异体心脏移植的归宿，并导致心脏排斥。纳米技术领域 创造了前所未有的机会，为以变革性的方法改变 药物输送的景观。然而，纳米药物在心脏移植中的应用还有待进一步研究。 发展起来的。在过去的几年里，我们已经开发出了第一类纳米载体，用于输送 IMD转DLN和心脏移植具有显著的临床疗效。这些数据显著地支持了 拟议研究的可行性。在目标1中，我们计划确定并进一步改进IMD的交付 以进一步促进同种异体心脏移植的存活。拟议的研究将采用小鼠心脏移植。 模型，已建立的功能分析和复杂的成像研究，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 向DLN输送IMD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，我们将 利用独特的移植环境，我们可以在移植前将IMD直接输送到心脏器官 移植。这些创新的和临床上可行的方法首次能够更好地控制 器官的炎性环境显著延长了慢性排斥反应。我们相信这些研究已经 产生范式转变成果的潜力，使变革和创新的发展成为可能 改善心脏移植结果的方法。 好了！