Catheter for Large Volume Intraparenchymal Brain Therapies

用于大容量脑实质内治疗的导管

• 批准号: 8934196
• 负责人: Jim Stice
• 金额: $ 37.29万
• 依托单位: TWIN STAR TDS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934196
• 关键词: Acute; Adverse event; Affect; Alzheimer' s Disease; American; Animal Testing; Animals; Area; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Neoplasms; Brain region; Canis familiaris; Catheters; Cell Therapy; Central Nervous System Diseases; Chronic; Clinical; Clinical Research; Clinical Trials; Comparative Study; Convection; Data; Disease; Dose; Drug Delivery Systems; Experimental Models; Family suidae; Fiber; Glioma; Health; Human; Immunotoxins; In Vitro; Infusion procedures; Lesion; Letters; Malignant - descriptor; Modeling; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Operative Surgical Procedures; Outcome; Parkinson Disease; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Recurrence; Reflux; Research; Research Personnel; Safety; Side; Small Business Innovation Research Grant; Solutions; Sterility; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Tracer; base; biomaterial compatibility; brain tissue; brain volume; chemotherapy; clinical efficacy; comparative; contrast enhanced; design; gene therapy; human study; improved; in vivo; innovation; meetings; novel; prototype; standard of care; tumor; usability; white matter

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.

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。使用对流增强递送（CED）将药物输注到脑实质允许直接治疗病变，绕过血脑屏障。特别是，重要的新疗法和疾病需要大脑的大区域接受治疗剂量。已经进行了多项临床试验，使用CED在神经胶质瘤患者中递送大量化疗和免疫毒素，但由于几个原因，包括药物在组织中的不可预测的分散，实际药物递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。为了克服与异质组织中的常规CED导管相关的限制，申请人已经开发了用于改善药物递送的大孔中空纤维导管（maPHFC）。假设：申请人提出，maPHFC将克服当前CED导管用于治疗需要在组织中大量分布的脑部病症的局限性。初步数据：在申请人的先前研究中，与常规CED导管相比，多孔中空纤维导管（PHFC）在定位、预充和输注方面表现出上级性能。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具有独特的能力，可以穿过空隙并将治疗剂分布在空隙的两侧。一种创新的大孔PHFC（maPHFC），提供了几天的大分子输液没有闭塞已经开发和初步测试。具体目标：通过该提议的I期可行性研究，申请人期望开发maPHFC设计以满足急性环境中大量输注的人类使用要求，并通过实验室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maPHFC设计。maPHFC设计将根据专家设计输入最终确定，以满足人类使用要求。先前研究的关键设计变更将集中在改进预充、隧道期间的maPHFC稳定性以及针对大体积分布的maPHFC设计优化。目的2：体内maPHFC比较安全性和输注研究。将在正常猪脑中使用MR示踪剂输注评价maPHFC和对照导管。结果将用于比较安全性和分布容积。目标3：maPHFC设计验证测试。目的是生成FDA临床研究批准所需的试验数据。