A Novel Protein Delivery System for Therapy of Preeclampsia

用于治疗先兆子痫的新型蛋白质递送系统

基本信息

批准号：
10680373
负责人：
Gene Leflore Bidwell
金额：
$ 49.93万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680373
关键词：
Affect African Green Monkey Amino Acid Motifs Amino Acids Angiogenesis Inhibitors Angiogenic Proteins Animal Model Antiinflammatory Effect Binding Biological Availability Blood Circulation Brain Hypoxia-Ischemia Cardiovascular Physiology Cessation of life Characteristics Chimera organism Chimeric Proteins Chronic Circulation Disease Drug Carriers Drug Delivery Systems Drug Kinetics Drug Utilization Elastin Endothelial Cells Escherichia coli Failure Fetal Development Fetus Functional disorder Funding Generations Goals Hypertension I-kappa B Proteins In Vitro Infant Inflammation Inflammatory Inflammatory Response Interleukin-6 Ischemia Lead Left Measures Mediating Modeling Molecular Mechanisms of Action Molecular Weight Morbidity - disease rate Mothers NF-kappa B Nuclear Import Pathogenicity Pathway interactions Peptides Perinatal mortality demographics Phase Phosphorylation Physiological Placenta Plasma Polymers Pre-Eclampsia Pregnancy Premature Birth Primates Proline Protein Isoforms Proteins Proteinuria Rattus SUI1 gene Safety Seizures Signal Transduction System TNF gene Testing Therapeutic Therapeutic Agents Translations Treatment Efficacy VEGFA gene Vascular Endothelial Growth Factor B Vascular Endothelial Growth Factors Virulence Factors Work angiogenesis antagonist chemical synthesis cytokine delivery vehicle effective intervention efficacious treatment factor A fetal immunogenicity improved in vivo inflammatory milieu macromolecule mortality nonhuman primate novel novel therapeutics peptide drug perinatal morbidity placental transfer polypeptide pre-clinical preclinical trial pregnancy disorder pregnancy hypertension prevent response small molecule therapeutics targeted agent therapeutic protein

项目摘要

Abstract. Preeclampsia is a common hypertensive disorder of pregnancy and is one of the leading causes of maternal, fetal, and perinatal morbidity and mortality. Affecting ~8% of all pregnancies in the US, preeclampsia displays characteristic hypertension, proteinuria, and altered cardiovascular function and, if left unchecked, can lead to maternal seizures and death. There is currently no effective intervention for preeclampsia short of induced delivery of the fetus, which is why it is also a leading cause of premature birth. Improvements in preeclampsia management have been largely stifled due to deleterious effects of various proposed small molecule therapeutics on the developing fetus. The objective of the proposed studies is to develop a drug delivery system capable of stabilizing novel therapeutic agents in the maternal circulation while protecting them from entering the fetal circulation. The onset and progression of preeclampsia is driven by two major pathways, secretion of the VEGF antagonist sFlt-1 and induction of a highly inflammatory environment in the mother. We have developed novel agents targeting each of these pathways, a supplementary VEGF therapy to counteract the increased sFlt-1 levels and NF-κB inhibitory peptide therapy to block the inflammatory response. These therapeutics are attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes them in the maternal circulation while preventing them from crossing the placenta into the fetal circulation. During the first funding period, we assessed the therapeutic potential of one agent from each class, ELP fusion to VEGF-A121 to counteract sFlt-1 and an ELP fusion to a peptide that blocks NF-kB nuclear import to counteract the inflammatory signaling. We confirmed the activity of both agents in vitro, measured their in vivo pharmacokinetics and confirmed that ELP fusion prevents their placental transfer, and demonstrated their therapeutic efficacy in a rat model of preeclampsia. While both agents were effective in the rat model, we believe that each may be improved. For the ELP-fused VEGF, we hypothesize that a different, less angiogenic form of VEGF (VEGF-B167), will have more potent sFlt-1 binding while inducing less aberrant angiogenesis, thus making it a safer therapeutic option. For the NF-kB inhibitory peptides, we have generated five new peptides that target the NF-kB activation cascade a different levels, and we hypothesize that one (or a combination of multiple) of these peptides will have a more potent anti- inflammatory effect. During the renewal period, we will evaluate our second-generation agents in vitro to confirm their target binding and mechanism of action, assess their safety, pharmacokinetics, and therapeutic efficacy in our rat model of placental ischemia, and, in order to advance our lead agents toward translation, assess their safety and efficacy in a novel non-human primate model of gestational hypertension, the African Green Monkey.

抽象的。 Preclamsia是一种常见的妊娠高血压障碍，是孕产妇的主要原因之一胎儿，围产期发病率和死亡率。在美国的所有怀孕中影响约8％，先兆子痫显示特征性高血压，蛋白尿和心血管功能改变，如果不受组织检查，可能会导致孕产妇的癫痫发作和死亡。目前尚无诱发的先兆子痫的有效干预措施胎儿的递送，这也是为什么它也是早产的主要原因。先兆子痫的改善由于各种建议的小分子疗法的有害影响，管理层已被困在很大程度上。关于发育中的胎儿。拟议研究的目的是开发能够的药物输送系统稳定母体循环中的新型热剂，同时保护它们免于进入胎儿循环。先兆子痫的发作和进展是由两种主要途径驱动的，即VEGF的分泌拮抗剂SFLT-1和母亲高度炎症环境的诱导。我们已经开发了小说针对每种途径的代理，一种补充VEGF疗法来抵消SFLT-1的增加水平和NF-κB抑制性肽疗法可阻止炎症反应。这些治疗剂是附着的到称为弹性蛋白样的多肽（ELP）的药物输送载体，该载体在母体循环中稳定阻止他们将斑点越过胎儿循环。在第一个资金期间，我们评估了每个班级中一个药物的治疗潜力，ELP融合到VEGF-A121，以抵消SFLT-1和ELP 融合到阻塞NF-KB核进口以抵消炎症信号传导的肽。我们确认了两种药物在体外的活性，测量了它们的体内药代动力学，并确认ELP融合可防止它们的胎盘转移，并在先兆子痫的大鼠模型中证明了他们的治疗效率。两者兼而有之代理在大鼠模型中有效，我们认为每个人都可以改善。对于ELP融合的VEGF，我们假设一种不同的，较少的血管生成形式的VEGF（VEGF-B167）将具有更多的潜在SFLT-1结合虽然诱导了较少的异常血管生成，从而使其成为更安全的治疗选择。对于NF-KB抑制肽，我们已经产生了五个针对NF-KB激活级联的新宠物，并且我们假设这些宠物中的一个（或多个）的一个（或多个组合）将具有更大的潜在抗炎症作用。在续签期间，我们将在体外评估第二代药物以确认他们的目标结合和作用机理，评估其安全性，药代动力学和治疗效率我们的大鼠局部缺血模型，为了使我们的主要代理商朝着翻译迈进非洲绿色猴子的新型非人类私人私人模型中的安全性和效率。