Catheter for Large Volume Intraparenchymal Brain Therapies

描述（由申请人提供）：中枢神经系统的神经退行性和恶性疾病影响数百万美国人。这些疾病往往是毁灭性的，难以治疗，有效的药物输送仍然是一个重大挑战。使用对流增强输送（CED）将药物输注到脑实质中，可以绕过血脑屏障直接治疗病变。特别是，重要的新疗法和疾病需要对大脑的大区域进行治疗剂量。已经进行了多次临床试验，使用CED向胶质瘤患者输送大量化疗药物和免疫毒素，但由于药物在组织中的不可预测的分散，实际的药物输送到肿瘤的效果很差。这些不良事件导致疗效降低和毒性增加。为了克服传统CED导管在异质组织中的局限性，申请人开发了一种大孔中空纤维导管（mapfc），以改善药物输送。假设：申请人提出mapfcs将克服当前CED导管的局限性，用于治疗需要在组织中大面积分布的脑部疾病。初步数据：在申请人之前的研究中，与传统的CED导管相比，多孔中空纤维导管（phfc）在定位、启动和输注方面表现出优越的性能。在实验和大型动物研究中，phfc产生的反流较少。体外和体内研究表明，PHFC具有独特的能力，可以穿过空洞，并在空洞的两侧分配治疗药物。一种创新的大孔PHFC （maPHFC）已经开发出来，并进行了初步测试，可以提供几天的大分子无闭塞输注。具体目标：在这个拟议的I期可行性研究中，申请人希望开发mapfc设计，以满足急性环境下大量输液的人类使用要求，并通过实验和动物试验评估性能。将进行设计验证测试，以促进最终的临床研究。目标1：完成人类mapfc设计。mapfc设计将最终确定，以满足基于专家设计输入的人类使用需求。先前研究的关键设计变化将集中在改进的引射，隧道过程中的maPHFC稳定性以及大体积分布下maPHFC设计的优化。目的2：体内maPHFC安全性和输注比较研究。mapfc和对照导管将通过磁共振示踪剂输注在正常猪脑中进行评估。结果将用于比较安全性和分发量。目标3:mapfc设计验证测试。目的是生成FDA临床研究批准所需的测试数据。

DESCRIPTION (provided by applicant): Neurodegenerative and malignant diseases of the central nervous system affect millions of Americans. These diseases are often devastating and difficult to treat, and effective drug delivery remains a significant challenge. Infusion of drugs nto the brain parenchyma using convection-enhanced delivery (CED) allows direct treatment of lesions, circumventing the blood brain barrier. In particular, important new treatments and diseases call for large regions of brain to be subjected to therapeutic doses. Multiple clinical trials have been conducted using CED to deliver large volumes of chemotherapy and immunotoxins in patients with gliomas, but actual drug delivery to the tumor has been poor for several reasons including the unpredictable dispersion of the drug in the tissue. These adverse events result in reduced efficacy and increased toxicity. To overcome the limitations associated with conventional CED catheters in heterogeneous tissue, the Applicants have developed a macroporous hollow fiber catheter (maPHFC) for improved drug delivery. Hypothesis: The Applicants propose that maPHFCs will overcome the limitations of current CED catheters for the treatment of brain disorders requiring large distributions in tissue. Preliminary Data: In Applicant's prior research, porous hollow fiber catheters (PHFCs) showed superior performance in positioning, priming, and infusion as compared to conventional CED catheters. PHFCs produced less reflux in bench and large animal studies. In vitro and in vivo studies have shown the unique ability of the PHFC to traverse voids and distribute therapeutics across both sides of the void. An innovative macroporous PHFC (maPHFC) that provides several days of infusion of large molecules without occlusion has been developed and preliminarily tested. Specific Aims: With this proposed Phase I feasibility research, the Applicants expect to develop the maPHFC design to meet human use requirements for large infusions in acute settings and assess performance with bench and animal testing. Design verification testing will be conducted to facilitate eventual clinical studies. Aim 1: Finalize human maPHFC designs. maPHFC designs will be finalized to meet human use requirements based on expert design input. Key design changes from prior research will focus on improved priming, maPHFC stabilization during tunneling and optimization of the maPHFC design for large volume distribution. Aim 2: In vivo maPHFC comparative safety and infusion studies. maPHFC and control catheters will be evaluated in normal swine brains with MR tracer infusions. Results will be used to compare safety and volume of distribution. Aim 3: maPHFC design verification testing. The objective is to generate the test data required for FDA clinical study approvals.