Directed Antifungal Therapy for HIV-associated Cryptococcal Meningitis

 描述（由申请方提供）：HIV相关隐球菌性脑膜炎的定向抗真菌治疗PI：Lad、Shivanand和McCabe，Aaron项目总结隐球菌病是一种重要的系统性真菌病，是人类免疫缺陷病毒（HIV）阳性个体中最常见的传染病之一。在2500万艾滋病毒/艾滋病患者中，最近的估计表明，全球每年有100万例CM病例，每年有70万人死亡。HIV相关CM的死亡率仍然高得令人无法接受，尽管使用了基于阿朴霉素B（AMB）的治疗和抗逆转录病毒治疗（ART）。除了活性抗真菌治疗的渗透和循环不良外，脑脊液（CSF）开放压升高是另一个关键因素。认为病理生理学源于高活性CSF微生物负荷（1 × 106 CFU/ml）与微生物和多糖包膜沿蛛网膜绒毛沿着阻塞CSF流出的组合。连续高容量腰椎穿刺和其他CSF分流术可立即缓解症状并逆转神经系统疾病。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）处理和药物输送平台，将快速清除特定病原体，用于治疗生命 威胁中枢神经系统（CNS）的感染。重要的是，最近建议鞘内AMB的连续输注可以更快速和完全地清除感染，而没有与限制其临床应用的鞘内AMB推注相关的毒性。拟议项目的目标是开发一种系统，直接向CSF输送和循环靶向抗真菌治疗（AMB），并在CM动物模型中评价药物浓度和微生物负荷。总之，神经单采术是一种创新的治疗选择，可直接进入CSF，并结合靶向病原体清除创造主动循环。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。本I期STTR的成功完成将为II期CM治疗的更广泛临床前研究和GLP质量体系的开发提供数据。将同时开展监管、临床规划和报销工作，为试验用器械豁免（IDE）申请做准备。该项目的长期目标是开发一种新的杀真菌方法，快速降低全球HIV相关CM患者的CSF真菌负荷、发病率和死亡率。

 DESCRIPTION (provided by applicant): Directed Antifungal Therapy for HIV-associated Cryptococcal Meningitis PI: Lad, Shivanand and McCabe, Aaron Project Summary Cryptococcosis is an important systemic mycosis and one of the most prevalent infectious diseases in human immunodeficiency virus (HIV)-positive individuals. Amongst the 25 million people with HIV/AIDS, recent estimates indicate that there are 1 million cases of CM globally per year, with 700,000 deaths per year. The mortality of HIV-associated CM remains unacceptably high, despite amphotericin B (AMB)-based therapy and access to antiretroviral therapy (ART). In addition to poor penetration and circulation of active antifungal therapies, elevated cerebrospinal fluid (CSF) opening pressure is another critical factor. The pathophysiology is thought to stem from a combination of high active CSF organism burden (1x106 CFU/ml) combined with obstruction of CSF outflow by organism and polysaccharide capsule along the arachnoid villi. Serial high volume lumbar punctures and other CSF diversion procedures can produce immediate symptom relief as well as reversing neurological morbidity. 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 and drug delivery platform, that will rapidly clear specific pathogens for treating life threatening infections of the central nervous system (CNS). Importantly, continuous infusion of intrathecal AMB was recently suggested to clear infection more rapidly and completely, without the toxicities associated with intrathecal AMB boluses that have limited its clinical application. The objectives of the proposed project are to develop a system to deliver and circulate targeted antifungal therapies (AMB) directly to the CSF and evaluate drug concentration as well as organism burden in a CM animal model. In summary, Neurapheresis is an innovative therapeutic option that provides direct access to the CSF and creates active circulation combined with targeted pathogen removal. This treatment is intended to be complimentary and does not replace standard of care with systemic, intravenous antifungal regimens. Successful completion of this Phase I STTR will provide the data to justify broader preclinical studies and development of a GLP-quality system for treatment of CM in Phase II. Concurrent regulatory, clinical planning, and reimbursement work will be conducted to prepare for an investigational device exemption (IDE) application. The long-term goal of the project is to develop a novel fungicidal approach that rapidly reduces CSF fungal burden, morbidity and mortality for HIV-associated CM patients worldwide.