Validation of Novel Therapeutic Approach for Cryptococcal Meningitis

隐球菌性脑膜炎新治疗方法的验证

• 批准号: 9255531
• 负责人: Shivanand P Lad
• 金额: $ 100万
• 依托单位: MINNETRONIX, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-17 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255531
• 关键词: Adverse effects; Affect; Africa; Amphotericin B; Animal Model; Animals; Antibiotics; Antifungal Agents; Antifungal Therapy; Antigens; Blood Circulation; Catheters; Central Nervous System Infections; Cephalic; Cerebrospinal Fluid; Chairperson; Clinical; Clinical Pathways; Clinical Research; Clinical Trials; Collaborations; Colony-forming units; Combined Modality Therapy; Communicable Diseases; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Custom; Data; Development; Device or Instrument Development; Devices; Doctor of Philosophy; Drug resistance; Effectiveness; Ensure; Equilibrium; Excision; Exclusion; Filtration; Flucytosine; Future; Goals; Guidelines; HIV; Histologic; Hour; Human; Immunocompromised Host; In Vitro; Infection; Inflammatory; Instruction; Intervention; Interview; Intravenous; Invaded; Investigation; Life; Local Therapy; Measurement; Medical Device; Modeling; Morbidity - disease rate; Neuraxis; Neurologic; Neurosurgeon; Opportunistic Infections; Oral; Organ Transplantation; Organism; Oryctolagus cuniculus; Patients; Phase; Preparation; Procedures; Regimen; Research; Sampling; Small Business Technology Transfer Research; Southeastern Asia; Specialist; Speed; Spinal; Sterilization; System; Testing; Time; Training; Translating; Universities; Validation; Work; base; cerebrospinal fluid flow; data modeling; design; fluid flow; human study; in vivo; innovation; meetings; mortality; nervous system disorder; neurosurgery; novel therapeutic intervention; novel therapeutics; pathogen; portability; pre-clinical; radiologist; standard of care

Validation of a Novel Therapeutic Approach for Cryptococcal Meningitis PI: Lad, Shivanand and McCabe, Aaron Project Summary 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 an estimated 2600-7800 US cases and 400,000 cases of CM worldwide annually, with estimated mortality of 15-50% 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 II STTR in collaboration with experts from the Infectious Diseases and Neurosurgery Departments at Duke University. Phase I demonstrated the dramatic results of Neurapheresis, a cerebrospinal fluid (CSF) processing platform, with rapid clearance of organisms both in vitro and in vivo, in a rabbit CM model. Phase II will optimize and validate a tailored human system to target and rapidly remove C. neoformans from the CSF. Specific Aim 1 will demonstrate in vivo reduction of CSF fungal colony forming units and Cryptococcal antigen in a pivotal animal study using a validated rabbit CM model. Specific Aim 2 will demonstrate the computational fluid and flow dynamics of Cryptococcal clearance using a bench-top human cranial/spinal model. Specific Aim 3 will focus on completing development of a tailored human Neurapheresis system for reduction of CSF infection burden. 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 II STTR will provide Minnetronix with the ability to complete development of a GLP-quality system for the treatment of CM. 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.

隐球菌性脑膜炎新型治疗方法的验证PI：Lad，Shivanand和McCabe，Aaron 项目摘要 当隐球菌表现为隐球菌性脑膜炎（CM）时，它会造成很大的死亡率负担， 目前估计有2600 - 7800名美国人， 全球每年有400，000例CM病例，估计每年死亡率为15 - 50%。cm是 当新型隐球菌（一种担子菌真菌病原体）侵入中枢神经时引起 系统（CNS）。它最常见于免疫功能低下的患者，如艾滋病毒感染者或 器官移植目前的治疗包括抗真菌剂，其在渗透方面的效果有限。 中枢神经系统和各种全身性副作用。在治疗的前14天内减少病原体负荷， 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， 与来自杜克大学传染病和神经外科部门的专家合作。 第一阶段展示了神经单采术（一种脑脊液（CSF）处理平台）的显著结果， 在兔CM模型中，在体外和体内均快速清除微生物。第二阶段将优化和 验证一个定制的人类系统来瞄准并快速去除C。脑脊液中的新生儿具体目标1将 在关键动物中证明CSF真菌菌落形成单位和隐球菌抗原的体内减少 使用经验证的兔CM模型进行研究。具体目标2将展示计算流体和流动 使用台式人体颅骨/脊柱模型的隐球菌清除动力学。具体目标3将重点 完成定制的人类神经单采系统的开发，以减少CSF感染负担。 神经单采术是一种创新的新治疗选择，可直接进入CSF， 积极的循环，结合有针对性的病原体清除。这种治疗是为了补充 并且不能用全身性静脉内抗真菌治疗方案取代标准治疗（SOC）干预。 成功完成第二阶段STTR将使Minnetronix能够完成开发 GLP-质量体系用于治疗CM。同时进行监管、临床规划和报销 在阶段结束时，将开展工作以准备试验用器械豁免（IDE）申请 二.该项目的长期目标是开发一种新的治疗方法， 真菌负担，并转化为降低发病率和死亡率的CM患者在世界范围内。