Selective Cytopheresis Therapy in Systemic Inflammatory Response Syndrome

描述(申请人提供)：白细胞(LE)是许多临床炎症性疾病的发病和进展的主要因素，包括全身炎症反应综合征、败血症和急性呼吸窘迫综合征。需要新的和创新的疗法来治疗这些炎症性疾病状态，这提供了一个巨大的商业市场机会。大量的治疗方法正在研究中，以限制LE在炎症部位的激活和组织积聚，以最大限度地减少组织破坏和疾病进展。在体外血液循环中的一种治疗装置，称为选择性细胞遗传学装置(SCD)，隔离剂在低钙环境中激活LE，并抑制其炎症蛋白和细胞因子的释放。这项第二阶段研究方案建立在第一阶段目标的基础上，该目标成功地证明了第一代SCD1G在感染性休克的大型动物模型中具有更好的治疗效果，与假手术对照组相比，它具有更大的表面积(SA)，此外还建立了简化的SCD体外电路，以便在 标准护理医院设置。这项第二阶段提案将决定第二代SCD2G的设计和制造。定制的SCD2G设计将保持低剪切力和低离子钙环境，这被证明对SCDG1有效，除了减少血液填充量之外，还包括流动路径、流速、填充密度和SA，这是SCD1G商业中空纤维盒无法实现的。较低的血液充盈量和血流速度要求，将允许SCD2G治疗通过外周插入的中心导管(PICC线路)进行，或对血液动力学不稳定的危重患者进行治疗。SCD2G设计将通过计算流动动力学模拟在Silico中进行评估，以评估套管设计和内部设备几何形状。将制造原型并进行流动可视化研究，以确定具有有利流动轮廓的设计(目标1)。使用新鲜血液的体外血液循环将用于评估从计算机研究中挑选出来的SCD2G设计，以了解血液相容性和LE结合特性(目标2)。最后，选定的SCD2G设计将在第一阶段研究中使用的感染性休克猪模型中进行评估。在不同SA的SCDG2设计和SCDG1(目标3)之间，将比较各种肾脏和心血管参数、肺部炎症、细胞因子水平、系统中性粒细胞激活负荷和死亡时间。SCDG1疗法在三项探索性临床试验中表现出极好的安全性和令人信服的疗效，将死亡率从控制率的60%降至30%。 需要持续肾脏替代治疗的急性肾功能衰竭的ICU患者；这些患者中有50%-60%也是败血症。这项提案将确定最终的SCD2G设计，用于治疗广泛的脓毒症、严重脓毒症和感染性休克患者，并将为向FDA申请用于治疗脓毒症的SCD的IDE批准提供数据。

DESCRIPTION (provided by applicant): Leukocytes (LE) are major contributors to the pathogenesis and progression of many clinical inflammatory disorders, including the systemic inflammatory response syndrome, sepsis and acute respiratory distress syndrome. The need for new and innovative therapies to treat these inflammatory disease states presents a large commercial market opportunity. A large number of therapeutic approaches are under investigation to limit the activation and tissue accumulation of LE at sites of inflammation in order to minimize tissue destruction and disease progression. A therapeutic device within an extracorporeal blood circuit, called the selective cytopheretic device (SCD), sequesters activated LE in a low calcium environment and inhibits their release of inflammatory proteins and cytokines. This Phase II research proposal builds on the Phase I goals which successfully demonstrated the 1st generation SCD1G to have greater therapeutic efficacy with increasing surface area (SA) in a large animal model of septic shock, when compared to sham treated controls, in addition to establishing a simplified SCD extracorporeal circuit for ease of use under standard-of- care hospital settings. This Phase II proposal will determine the design and fabrication of a 2nd Generation SCD2G. Custom SCD2G designs will maintain the low shear force and low ionized calcium environment, shown to be efficacious for SCDG1, with variations to include flow path, flow rates, packing density, and SA, in addition to reduced blood fill volumes which were not achievable with the SCD1G commercially available hollow fiber cartridges. The lower blood fill volume and blood flow rate requirements, will allow SCD2G therapy to be administered via a peripherally inserted central catheter (PICC line) or to criticall ill patients with hemodynamic instability. SCD2G designs will be evaluated in silico via computational flow dynamics simulation to assess casing design and internal device geometry. Prototypes will be fabricated and flow visualization studies performed to determine designs with advantageous flow profiles (Aim 1). In vitro blood circuits with fresh blood will be used to evaluate SCD2G designs selected from in silico studies with respect to hemocompatibility and LE binding characteristics (Aim 2). Lastly, selected SCD2G designs will be evaluated in the porcine model of septic shock used in the Phase I studies. Various renal and cardiovascular parameters, pulmonary inflammation, cytokine levels, systemic neutrophil activation load and time to death will be compared between SCDG2 designs of varying SA and the SCDG1 (Aim 3). SCDG1 therapy has demonstrated an excellent safety profile and compelling efficacy impact in three exploratory clinical trials, reducing mortality rates from the control rate of 60% to 30%, in ICU patients with acute renal failure requiring continuous renal replacement therapy; 50-60% of these patients were also septic. This proposal will determine a finalized SCD2G design to treat a broad array of patients with sepsis, severe sepsis and septic shock and will provide data for an application to the FDA for IDE approval for the SCD to be used in the treatment of sepsis.