Validation of Novel Therapeutic Approach for Cryptococcal Meningitis

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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.