Development of a Novel Therapeutic Approach for Cryptococcal Meningitis

 描述（由申请人提供）：当隐球菌表现为隐球菌性脑膜炎（CM）时，它给患者带来了巨大的死亡率和发病率负担，临床医生很难治疗。目前美国每年有10，000例CM病例，全球每年有超过100万例CM病例，估计每年有700，000例死亡。CM是由新型隐球菌（Cryptococcus neoformans）（一种担子菌真菌病原体）侵入中枢神经系统（CNS）引起的，最常见于免疫功能低下的患者，如HIV感染者或器官移植后的患者。目前的治疗方法包括抗真菌药物，这些药物穿透中枢神经系统的效果有限，并有各种全身副作用。治疗前14天内病原体负荷的减少是发病率和死亡率降低的最佳预测因素。Minnetronix是一家医疗设备开发和制造公司，它与杜克大学传染病和神经外科部门的专家合作提出了这一第一阶段STTR。第一阶段将专注于开发神经单采术，这是一种脑脊液（CSF）处理平台，将快速清除特定病原体，用于治疗危及生命的中枢神经系统（CNS）感染。拟议项目的目标是开发一个定制的系统，以针对和消除C。从CSF中分离新生儿并评估其在CM动物模型中的减少。具体目标1将侧重于使用为隐球菌排除量身定制的设计矩阵进行体外测试。将进行寿命和机械测试，以确保安全性和可靠性。第2章评价 在经验证的兔CM模型中CSF真菌CFU的体内减少。总之，神经单采术是一种创新的新治疗选择，可直接进入CSF，并结合靶向病原体清除创造活跃的循环。这种治疗是补充性的，不会用全身性静脉内抗真菌治疗方案取代标准治疗（SOC）干预。本I期STTR的成功完成将为Minnetronix提供数据，以证明更广泛的临床前研究和II期CM治疗GLP质量体系的开发是合理的。在II期期间，将同时开展监管、临床规划和报销工作，以准备II期结束时的试验用器械豁免（IDE）申请。该项目的长期目标是开发一种新的治疗方法，快速降低CSF真菌负荷，并降低全球CM患者的发病率和死亡率。

 DESCRIPTION (provided by applicant): When Cryptococcus is manifested as Cryptococcal meningitis (CM), it creates a large burden of mortality and morbidity to the patient and is very difficult for the clinician to treat. There are now 10,000 US cases and over 1 million cases of CM worldwide annually, with estimated deaths of 700,000 per year. CM is caused when Cryptococcus neoformans, a basidiomycete fungal pathogen, invades the central nervous system (CNS), It is seen most commonly in immunocompromised patients, such as those with HIV or post organ-transplant. Current treatments include anti-fungal agents that have limited effectiveness in penetrating the CNS and various systemic side effects. Reduction in pathogen burden within the first 14 days of therapy is the best predictor of reduced morbidity and mortality. Minnetronix, a medical device development and manufacturing company, proposes this Phase I STTR in collaboration with experts from the Infectious Diseases and Neurosurgery Departments at Duke University. Phase I will focus on developing Neurapheresis, a cerebrospinal fluid (CSF) processing platform, that will rapidly clear specific pathogens for treating life-threatening infections of the central nervous system (CNS). The objective of the proposed project is to develop a tailored system to target and remove C. neoformans from the CSF and to evaluate its reduction in a CM animal model. Specific Aim 1 will focus on conducting in vitro testing using a design matrix tailored for Cryptococcus exclusion. Longevity and mechanical testing will be performed to ensure safety and reliability. Specific Aim 2 will evaluate the in vivo reduction of CSF fungal CFUs in a validated rabbit CM model. In summary, Neurapheresis is an innovative, new therapeutic option that provides direct access to the CSF and creates active circulation combined with targeted pathogen removal. This treatment is intended to be complementary and does not replace standard of care (SOC) interventions with systemic, intravenous antifungal regimens. Successful completion of this Phase I STTR will provide Minnetronix with the data to justify broader preclinical studies and development of a GLP-quality system for treatment of CM in Phase II. During Phase II, concurrent regulatory, clinical planning, and reimbursement work will be conducted to prepare for an investigational device exemption (IDE) application at the end of Phase II. The long-term goal of the project is to develop a novel therapeutic approach that rapidly reduces CSF fungal burden and translates to reduced morbidity and mortality for CM patients worldwide.