Development of a Novel Therapeutic Approach for Cryptococcal Meningitis

 描述(申请人提供)：当隐球菌表现为隐球菌性脑膜炎(CM)时，它给患者造成了很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100多万例CM病例，估计每年有70万人死亡。CM是当一种担子真菌病原体新生隐球菌入侵中枢神经系统(CNS)时引起的，最常见于免疫功能低下的患者，如艾滋病毒携带者或器官移植后。目前的治疗方法包括抗真菌药物在穿透中枢神经系统方面效果有限，以及各种全身副作用。在治疗的前14天内减少病原体负担是降低发病率和死亡率的最佳预测指标。Minnetronix是一家医疗器械开发和制造公司，该公司与杜克大学传染病和神经外科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分离，这是一个脑脊液(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种量身定制的系统，以靶向并从脑脊液中清除新生葡萄球菌，并在CM动物模型中评估其减少。具体目标1将侧重于使用为排除隐球菌而量身定做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。《特定目标2》将评估 在经过验证的兔CM模型中，脑脊液真菌CFU的体内减少。总而言之，神经分离是一种创新的新治疗选择，它提供了直接进入脑脊液的途径，并结合靶向病原体清除创造了活跃的循环。这种治疗旨在起到补充作用，并不会用全身静脉抗真菌疗法取代标准护理(SOC)干预。第一阶段STTR的成功完成将为Minnetronix提供数据，以证明在第二阶段进行更广泛的临床前研究和开发用于治疗CM的GLP质量系统是合理的。在第二阶段，将同时进行监管、临床规划和报销工作，为第二阶段结束时的研究设备豁免(IDE)申请做准备。该项目的长期目标是开发一种新的治疗方法，迅速减少脑脊液真菌负担，并转化为降低全球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.