Directed Antifungal Therapy for HIV-associated Cryptococcal Meningitis

 描述(申请人提供)：HIV相关隐球菌性脑膜炎的定向抗真菌治疗PI：LAD、Shivanand和McCabe，Aaron项目摘要隐球菌病是一种重要的系统性霉菌病，也是人类免疫缺陷病毒(HIV)阳性患者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。尽管基于两性霉素B(AMB)的治疗和获得抗逆转录病毒治疗(ART)，艾滋病毒相关CM的死亡率仍然高得令人无法接受。除了主动抗真菌治疗的渗透性和循环性差之外，脑脊液(CSF)开放压力升高是另一个关键因素。病理生理学被认为是由于高活性脑脊液生物负荷(1x106CFU/ml)和沿蛛网膜绒毛的生物体和多糖膜阻塞脑脊液流出所致。连续的大容量腰椎穿刺术和其他脑脊液分流手术可以立即缓解症状，并逆转神经系统的发病率。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)处理和药物输送平台，将快速清除治疗生命的特定病原体 威胁到中枢神经系统(CNS)的感染。重要的是，最近有人建议鞘内持续输注AMB可以更快、更彻底地清除感染，而不会出现与鞘内注射AMB相关的毒性，限制了其临床应用。该项目的目标是开发一种系统，将靶向抗真菌疗法(AMB)直接输送到脑脊液，并在CM动物模型中评估药物浓度和生物负荷。总而言之，神经分离是一种创新的治疗选择，它提供了直接进入脑脊液的途径，并结合有针对性的病原体清除创造了活跃的循环。这种治疗是免费的，并不会用全身静脉抗真菌疗法取代标准的护理。这一第一阶段STTR的成功完成将提供数据，证明在第二阶段进行更广泛的临床前研究和开发治疗CM的GLP质量系统是合理的。同时将进行监管、临床规划和报销工作，为研究设备豁免(IDE)申请做准备。该项目的长期目标是开发一种新的杀菌方法，迅速降低全球艾滋病毒相关CM患者的脑脊液真菌负担、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.