Testing of a New Protein Drug for Toxin-Induced Sepsis

测试一种新的蛋白质药物治疗毒素引起的败血症

• 批准号: 6645252
• 负责人: J. Joseph Kim
• 金额: $ 9.03万
• 依托单位: VIRAL GENOMIX, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6645252
• 关键词: Macaca; affinity chromatography; antibacterial agents; blood toxicology; drug design /synthesis /production; drug screening /evaluation; enzyme linked immunosorbent assay; laboratory mouse; lipopolysaccharides; pathologic process; recombinant proteins; septic shock; septicemia; staphylococcal enterotoxin; tissue /cell culture

DESCRIPTION (provided by applicant): Sepsis or septic shock is a complex cascade of adverse host systemic inflammatory responses induced by infection. Severe sepsis is the most common type found in the intensive care unit (ICU) and it is a common, frequently fatal and expensive disease. In fact, severe sepsis is the number one cause of death in the non-coronary intensive care unit and the 11th leading cause of death overall in the US. Recent studies report that there are at least 750,000 new cases of severe sepsis annually in the United States with more than 2,000 new cases per day. Progression of sepsis can lead to organ dysfunction and ultimately death. Mortality from severe sepsis ranges from 30% to 50% or greater. We have developed VGX-300 (recombinant Vpr protein), as a potential novel therapy for Sepsis. We believe VGX- 300 has important therapeutic qualities relevant to the pathogenesis of severe sepsis. Our company has a diverse and proprietary patent position on the use of recombinant Vpr protein to treat sepsis and other inflammatory diseases. Successful completion of these Phase I studies will result in the demonstration of feasibility for using VGX-300 as a novel drug to treat sepsis. We will test our hypothesis through a collection of three specific aims using Staph Enterotoxin B (SEB) and Lipopolysaccharides (LPS) as model toxins from Gram-positive and Gram-negative bacteria, respectively. We will also test VGX-300's therapeutic effects against a polymicrobial challenge model. The three specific aims are: Aim I: Establish manufacturing process and potency assay for VGX-300 (recombinant Vpr protein), a potential novel therapy for Sepsis. Aim 2: Test the protective effects of VGX-300 in lethal toxin challenge models in mice. SEB and LPS will be used as model toxins for Gram-positive and -negative toxins, respectively. Aim 3: Test the protective effects of VGX-300 in mice against polybacterial sepsis challenge using the cecal ligation and puncture (CLP) model. This project will test the hypothesis that VGX-300 will be effective at preventing morbidity and mortality from toxin induced cytokine storm and sepsis in a murine model system. This proof of concept funding in this Phase I proposal will enable further testing of our company's drug candidate for sepsis in the Phase II funding of SBIR. With successful characterization of the protective effects of VGX-300 in Phase I of this SBIR, we will focus on bringing this product to clinical evaluation as expediently as possible. This would involve a scaling up of recombinant Vpr protein manufacturing process under both GLP and GMP conditions. In anticipation of carrying the Vpr protein into clinical evaluation, pre-clinical toxicity and pharmacokinetics studies in both mice and in macaques will also be performed as a part of Phase II studies. Lastly, we will be able to file an Investigative New Drug (IND) application for VGX-300 with the FDA at the conclusion of our Phase II studies.

描述（由申请人提供）：败血症或败血性休克是由感染引起的宿主不良全身炎症反应的复杂级联反应。严重败血症是重症监护病房 (ICU) 中最常见的类型，是一种常见、经常致命且昂贵的疾病。事实上，严重脓毒症是非冠心病重症监护室的第一大死因，也是美国第 11 大死因。最近的研究报告称，美国每年至少有 75 万例新发严重败血症病例，每天新增病例超过 2,000 例。脓毒症的进展可导致器官功能障碍并最终导致死亡。严重败血症的死亡率为 30% 至 50% 或更高。 我们开发了 VGX-300（重组 Vpr 蛋白），作为脓毒症的潜在新型疗法。我们相信 VGX-300 具有与严重脓毒症发病机制相关的重要治疗特性。我们公司在使用重组 Vpr 蛋白治疗脓毒症和其他炎症性疾病方面拥有多样化的专有专利地位。这些 I 期研究的成功完成将证明使用 VGX-300 作为治疗脓毒症的新药的可行性。我们将分别使用葡萄球菌肠毒素 B (SEB) 和脂多糖 (LPS) 作为革兰氏阳性菌和革兰氏阴性菌的模型毒素，通过三个特定目标的集合来检验我们的假设。我们还将测试 VGX-300 针对多种微生物挑战模型的治疗效果。这三个具体目标是： 目标 I：建立 VGX-300（重组 Vpr 蛋白）的生产工艺和效力测定，VGX-300 是一种潜在的败血症新疗法。 目标 2：测试 VGX-300 在小鼠致命毒素激发模型中的保护作用。 SEB和LPS将分别用作革兰氏阳性毒素和革兰氏阴性毒素的模型毒素。 目标 3：使用盲肠结扎穿刺 (CLP) 模型测试 VGX-300 对小鼠对抗多菌败血症攻击的保护作用。 该项目将测试以下假设：VGX-300 将在小鼠模型系统中有效预防毒素诱导的细胞因子风暴和败血症的发病率和死亡率。第一阶段提案中的概念验证资金将使我们公司能够在 SBIR 第二阶段资金中进一步测试败血症候选药物。 随着本次 SBIR 第一阶段成功表征 VGX-300 的保护作用，我们将致力于尽快将该产品投入临床评估。这将涉及在 GLP 和 GMP 条件下扩大重组 Vpr 蛋白生产工艺。为了将 Vpr 蛋白纳入临床评估，作为 II 期研究的一部分，还将在小鼠和猕猴中进行临床前毒性和药代动力学研究。最后，在 II 期研究结束后，我们将能够向 FDA 提交 VGX-300 的研究性新药 (IND) 申请。