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不良宿主全身性炎症反应的复杂级联。严重的败血症是重症监护病房（ICU）中最常见的类型，它是一种常见，经常致命且昂贵的疾病。实际上，严重的败血症是非冠军重症监护病房的第一名死亡原因，也是美国总体上第11大死亡原因。最近的研究报告说，美国每年至少有750,000例新的严重败血症病例，每天有超过2,000例新病例。败血症的进展会导致器官功能障碍并最终导致死亡。严重败血症的死亡率范围为30％至50％或更高。 我们已经开发了VGX-300（重组VPR蛋白），作为一种潜在的败血症治疗方法。我们认为VGX-300具有与严重败血症发病机理有关的重要治疗质量。我们公司在使用重组VPR蛋白治疗败血症和其他炎症性疾病方面具有多样化且专有的专利立场。成功完成这些I期研究将导致证明使用VGX-300作为一种新型药物治疗败血症的可行性。我们将分别使用葡萄球菌肠毒素B（SEB）和脂多糖（LPS）作为模型毒素的三个特定目标来检验我们的假设，分别是革兰氏阳性和革兰氏阴性细菌的模型毒素。我们还将测试VGX-300针对多生物挑战模型的治疗作用。三个具体目的是：目标I：建立VGX-300（重组VPR蛋白）的制造过程和效力测定，这是一种潜在的败血症的新型疗法。 AIM 2：测试VGX-300在小鼠致命毒素挑战模型中的保护作用。 SEB和LPS将分别用作革兰氏阳性和阴性毒素的模型毒素。 AIM 3：使用Cecal连接和穿刺模型（CLP）模型测试VGX-300对小鼠败血症挑战的保护作用。 该项目将检验以下假设：VGX-300将有效预防毒素模型系统中毒素诱导的细胞因子风暴和败血症的发病率和死亡率。该阶段I提案中的概念资金证明将使我们公司在SBIR的II期资金中进一步测试我们公司的败血症药物候选人。 随着VGX-300在该SBIR的I期的成功表征，我们将重点放在尽可能方便地将该产品带到临床评估中。这将涉及在GLP和GMP条件下的重组VPR蛋白制造过程的扩展。期望将VPR蛋白携带到临床评估中，因此在小鼠和猕猴中的临床前毒性和药代动力学研究也将作为II期研究的一部分。最后，在我们的II期研究结束时，我们将能够向FDA提交调查性新药（IND）申请。