Simoni Jan, Simoni Grace, Moeller John F, Feola Mario, Wesson Donald E
Division of Artificial Oxygen Carriers, Texas HemoBioTherapeutics & BioInnovation Center (THBBC), Lubbock, TX, USA; School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Artif Organs. 2014 Aug;38(8):684-90. doi: 10.1111/aor.12337. Epub 2014 Jul 1.
Effective artificial oxygen carriers may offer a solution to tackling current transfusion medicine challenges such as blood shortages, red blood cell storage lesions, and transmission of emerging pathogens. These products, could provide additional therapeutic benefits besides oxygen delivery for an array of medical conditions. To meet these needs, we developed a hemoglobin (Hb)-based oxygen carrier, HemoTech, which utilizes the concept of pharmacologic cross-linking. It consists of purified bovine Hb cross-linked intramolecularly with open ring adenosine-5'-triphosphate (ATP) and intermolecularly with open ring adenosine, and conjugated with reduced glutathione (GSH). In this composition, ATP prevents Hb dimerization, and adenosine promotes formation of Hb polymers as well as counteracts the vasoconstrictive and pro-inflammatory properties of Hb via stimulation of adenosine receptors. ATP also serves as a regulator of vascular tone through activation of purinergic receptors. GSH blocks Hb's extravasation and glomerular filtration by lowering the isoelectric point, as well as shields heme from nitric oxide and reactive oxygen species. HemoTech and its manufacturing technology have been broadly tested, including viral and prion clearance validation studies and various nonclinical pharmacology, toxicology, genotoxicity, and efficacy tests. The clinical proof-of-concept was carried out in sickle cell anemia subjects. The preclinical and clinical studies indicate that HemoTech works as a physiologic oxygen carrier and has efficacy in treating: (i) acute blood loss anemia by providing a temporary oxygen bridge while stimulating an endogenous erythropoietic response; (ii) sickle cell disease by counteracting vaso-occlusive/inflammatory episodes and anemia; and (iii) ischemic vascular diseases particularly thrombotic and restenotic events. The pharmacologic cross-linking of Hb with ATP, adenosine, and GSH showed usefulness in designing an artificial oxygen carrier for multiple therapeutic indications.
有效的人工氧载体可能为应对当前输血医学面临的挑战提供解决方案，如血液短缺、红细胞储存损伤以及新兴病原体的传播。这些产品除了为一系列医疗状况提供氧气输送外，还可能带来额外的治疗益处。为满足这些需求，我们开发了一种基于血红蛋白（Hb）的氧载体HemoTech，它采用了药理学交联的概念。它由纯化的牛血红蛋白组成，分子内与开环腺苷-5'-三磷酸（ATP）交联，分子间与开环腺苷交联，并与还原型谷胱甘肽（GSH）共轭。在这种组合物中，ATP可防止血红蛋白二聚化，腺苷促进血红蛋白聚合物的形成，并通过刺激腺苷受体抵消血红蛋白的血管收缩和促炎特性。ATP还通过激活嘌呤能受体作为血管张力的调节剂。GSH通过降低等电点来阻止血红蛋白的外渗和肾小球滤过，并保护血红素免受一氧化氮和活性氧的影响。HemoTech及其制造技术已进行了广泛测试，包括病毒和朊病毒清除验证研究以及各种非临床药理学、毒理学、遗传毒性和疗效测试。临床概念验证在镰状细胞贫血患者中进行。临床前和临床研究表明，HemoTech作为一种生理性氧载体发挥作用，在治疗以下疾病方面具有疗效：（i）急性失血性贫血，通过提供临时氧桥同时刺激内源性红细胞生成反应；（ii）镰状细胞病，通过抵消血管闭塞/炎症发作和贫血；（iii）缺血性血管疾病，特别是血栓形成和再狭窄事件。血红蛋白与ATP、腺苷和GSH的药理学交联在设计用于多种治疗适应症的人工氧载体方面显示出实用性。
