Catheter for Large Volume Intraparenchymal Brain Therapies

描述(申请人提供)：中枢神经系统退行性疾病和恶性疾病影响数百万美国人。这些疾病往往具有破坏性，难以治疗，有效的药物输送仍然是一个重大挑战。使用对流增强递送(CED)将药物注入脑实质，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片区域进行治疗剂量。已经进行了多项临床试验，使用CED在胶质瘤患者体内输送大量的化疗和免疫毒素，但由于几个原因，实际的药物输送一直很差，包括药物在组织中的不可预测的分散。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，申请人开发了一种用于改善药物输送的大孔中空纤维导管(MaPHFC)。假设：申请人提出，maPHFC将克服目前CED导管的局限性，用于治疗需要在组织中大分布的脑部疾病。初步资料：在申请者先前的研究中，与传统的CED导管相比，多孔中空纤维导管(PHFC)在定位、预充和输液方面表现出更好的性能。在实验室和大型动物研究中，PHFC产生的反流较少。体外和体内研究表明，PHFC具有穿越空洞并将治疗药物分布到空洞两侧的独特能力。一种创新的大孔PHFC(MaPHFC)已经开发出来并进行了初步测试，它可以提供几天无堵塞的大分子输注。具体目标：通过这项拟议的第一阶段可行性研究，申请者希望开发maPHFC设计，以满足急性环境中大量输液的人类使用要求，并通过试验台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：最终确定人类maPHFC的设计。MaPHFC的设计将根据专家的设计意见最终确定，以满足人类的使用要求。与先前研究相比，设计的主要变化将集中在改进的引爆、隧道施工期间maPHFC的稳定以及针对大容量分布的maPHFC设计的优化。目的2：体内MAPHFC的比较安全性和输注研究。MaPHFC和对照导管将通过磁共振示踪剂注射在正常猪的大脑中进行评估。结果将被用来比较分配的安全性和数量。目标3：MaPHFC设计验证测试。目标是生成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.