Self-replicating RNA-nanoplexes for programming monocytes to regenerate the heart

用于编程单核细胞以再生心脏的自我复制RNA纳米复合物

• 批准号: 8968584
• 负责人: Juliane Nguyen
• 金额: $ 23.6万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968584
• 关键词: Area; Blood Circulation; Blood Vessels; Blood flow; Cardiac; Cardiac Myocytes; Clinical Research; Deposition; Dose; Drug Carriers; Drug Delivery Systems; Encapsulated; Engineering; Extracellular Matrix; Goals; Half-Life; Heart; Heart Transplantation; Home environment; Homing; Hyperplasia; Hypertrophy; Hypoxia; Implant; Infarction; Inflammation; Injection of therapeutic agent; Internal Ribosome Entry Site; Lead; Libraries; Life; Ligands; Lipids; Mediating; Messenger RNA; Methods; Mitosis; Mole the mammal; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; NRG1 gene; Natural regeneration; Neuregulins; Outcome; Oxygen; Patients; Peptide Signal Sequences; Permeability; Pharmaceutical Preparations; Production; Proliferating; Proteins; RNA; Reaction Time; Research; Risk; Site; Surface; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Transgenes; Treatment Efficacy; Vascular blood supply; biomaterial compatibility; cardiac repair; conventional therapy; density; heart cell; heart function; improved; in vivo; innovation; killings; monocyte; mouse model; novel; novel strategies; novel therapeutics; programs; public health relevance; receptor; response; screening; therapeutic protein; tissue regeneration

 DESCRIPTION: There are currently no treatments capable of restoring cardiac function after myocardial infarction (MI) besides cardiac transplantation. MI kills millions of heart cells due to reduced oxygen and blood supply. Strategies to regenerate damaged heart cells that use proteins, such as neuregulin (NRG1), to stimulate mitosis of surviving cardiomyocytes could partially restore infarcted myocardium. However, delivering such therapeutics to the heart using conventional methods is difficult for two reasons: (1) heart blood vessels show very low permeability for large molecules, (2) molecules that do reach the heart are washed away rapidly by the high blood flow. In clinical studies, NRG1's short half-life necessitates daily systemic injections. Further, the fraction that reaches the heart is very low, compromising its therapeutic efficacy. This non-targeted approach can also lead to the uncontrolled proliferation of cardiomyocytes in the remote zone of the heart, causing myocardial hyperplasia and hypertrophy. Clearly there is an urgent need for a non-invasive and controlled delivery approach that can specifically target surviving cardiomyocytes in the infarcted area and border zone. We propose to develop a novel delivery strategy that fulfills this need. Our approach will target infarcted cardiac tissue by exploiting the body's immunological response to MI. Specifically, we propose to deliver regenerating proteins using monocytes that naturally migrate to the site of infarction. Monocytes show extraordinary retention in the heart in spite of high blood flow due to specific receptor-ligand interactions with the extracellular matrix and other proteins. We hypothesize that (1) monocytes can be targeted and genetically programmed with self-replicating RNA-nanoplexes to express NRG1 and that (2) monocytes will home to infarcted tissue and locally release NRG1, a protein that can induce cardiomyocyte proliferation and facilitate tissue regeneration. To test these hypotheses, we will first generate self-replicating RNA-nanoplexes that target monocytes and program them to express NRG1. Secondly, we will quantify the number of MI-homing monocytes that are genetically programmed for protein production in a mouse model of MI. We anticipate that these studies will lead to a living drug reservoir that is non-invasive and able to locally deliver protein therapeutics to the infarcted sie and its border zone. This has profound implications for the treatment of patients with IHD and the regeneration of infarcted myocardium.

 描述：目前，除心肌梗死（MI）之后，还没有能够恢复心脏功能的治疗方法。 MI由于 氧气和血液供应减少。再生使用蛋白质（NRG1）等蛋白质的受损心脏细胞的策略，以刺激生存性心肌细胞的有丝分裂，可能会部分恢复梗塞的心肌。然而，由于两个原因，很难使用常规方法将这种治疗剂递送到心脏：（1）心血管显示出大分子的渗透性非常低，（2）确实到达心脏的分子被高血流量迅速冲走。在临床研究中，NRG1的短期半衰期必要的每日全身注射。此外，到达心脏的分数非常低，提高了其治疗效率。这种非靶向方法还可能导致心脏偏远区域中心肌细胞的不受控制，从而导致心肌增生和肥大。显然，迫切需要一种非侵入性和受控的递送方法，该方法可以专门针对梗塞区域和边界区域中存活的心肌细胞。我们建议制定一种满足这一需求的新型交付策略。我们的方法将通过利用人体对MI的免疫反应来靶向梗塞心脏组织。具体而言，我们建议使用自然迁移到梗塞部位的单核细胞提供再生蛋白质。尽管特定的接收器配体与细胞外基质和其他蛋白质相互作用，但单核细胞在心脏中表现出非凡的保留率。我们假设（1）单核细胞可以通过自我复制的RNA纳米插曲来靶向和遗传编程以表达NRG1，并且（2）单核细胞将归为梗塞组织并局部释放的NRG1，这种蛋白质可以诱导心肌细胞的扩散和面部组织。为了检验这些假设，我们将首先生成靶向单核细胞和编程以表达NRG1的自我复制的RNA-nanoplexes。其次，我们将量化用于MI小鼠模型中蛋白质产生的遗传编程的MI养单核细胞的数量。我们预计，这些研究将导致无创的活力储层，并能够将蛋白质治疗局部提供给梗塞的SIE及其边界区。这对治疗IHD患者的治疗和梗塞心肌的再生具有深远的影响。