Testing of a New Protein Drug for Toxin-Induced Sepsis

描述(由申请人提供)：败血症或感染性休克是由感染引起的一系列复杂的不良宿主全身炎症反应。严重脓毒症是重症监护病房(ICU)中最常见的类型，也是一种常见的、往往致命的和昂贵的疾病。事实上，严重的脓毒症是非冠状动脉重症监护病房的头号死因，也是美国总的第11大死因。最近的研究报告说，美国每年至少有75万新的严重脓毒症病例，每天有2000多个新病例。脓毒症的进展可导致器官功能障碍，最终导致死亡。严重脓毒症的死亡率从30%到50%或更高。我们开发了VGX-300(重组VPR蛋白)，作为一种潜在的治疗脓毒症的新方法。我们认为VGX-300具有与严重脓毒症发病机制相关的重要治疗品质。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种专利地位。这些第一阶段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。我们将通过收集三个特定的目标来验证我们的假设，分别使用葡萄球菌肠毒素B(SEB)和脂多糖(LPS)作为革兰氏阳性和革兰氏阴性细菌的模型毒素。我们还将测试VGX-300‘S对多菌攻击模型的治疗效果。目的I：建立VGX-300(重组VPR蛋白)的制备工艺和效价测定，VGX-300是一种潜在的脓毒症新疗法。目的：检测VGX-300对小鼠致死毒素攻击模型的保护作用。SEB和LPS将分别作为革兰氏阳性和阴性毒素的模型毒素。目的：采用盲肠结扎穿孔(CLP)模型，检测VGX-300对小鼠多菌脓毒症的保护作用。该项目将在小鼠模型系统中测试VGX-300将有效预防毒素诱导的细胞因子风暴和脓毒症的发病率和死亡率的假设。这一第一阶段提案中的概念验证资金将使我们公司在SBIR第二阶段资金中用于脓毒症的候选药物得到进一步测试。随着VGX-300在这项SBIR的第一阶段中的保护作用的成功表征，我们将专注于将该产品尽可能方便地投入临床评估。这将涉及在GLP和GMP条件下扩大重组VPR蛋白的制造工艺。为了预期将VPR蛋白带入临床评估，还将在小鼠和猕猴中进行临床前毒性和药代动力学研究，作为第二阶段研究的一部分。最后，我们将能够在我们的第二阶段研究结束时向FDA提交VGX-300的研究新药(IND)申请。

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.