SBIR-STTR Award

?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.

Public Health Relevance Statement:


Public Health Relevance:
Directed Antifungal Therapy for HIV-associated Cryptococcal Meningitis PI: Lad, Shivanand and McCabe, Aaron Project Narrative In this Phase I STTR, Minnetronix plans to develop an innovative, new therapeutic platform for delivering and circulating antifungal therapies for devastating Central Nervous System (CNS) infections. Cryptococcal meningitis (CM) is one of the most prevalent infectious diseases in human immunodeficiency virus (HIV)- positive individuals. The mortality of HIV-associated CM remains unacceptably high, despite intravenous amphotericin B (AMB)-based therapy and access to antiretroviral therapy (ART). This project will provide the first-ever directed fungicidal platformfor HIV-associated CM and save lives.

NIH Spending Category:
Bioengineering; Infectious Diseases; Neurosciences

Project Terms:
Acquired Immunodeficiency Syndrome; Amphotericin B; Animal Model; Animals; Antibiotics; Antifungal Agents; Antifungal Therapy; antiretroviral therapy; arachnoid villi; Area; base; Blood Circulation; Bolus Infusion; capsule (pharmacologic); Catheters; Central Nervous System Infections; Cephalic; Cerebrospinal Fluid; cerebrospinal fluid flow; Cessation of life; Chest; Clinical; clinical application; Clinical Trials; Cohort Studies; Collaborations; Colony-forming units; Communicable Diseases; Continuous Infusion; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans infection; Custom; Data; design; Development; Device or Instrument Development; Devices; Diagnosis; Doctor of Philosophy; Dose; Drug Delivery Systems; Drug Kinetics; Ensure; Equilibrium; Excision; experience; Filtration; Functional disorder; Goals; HIV; Hour; In Vitro; in vitro testing; in vivo; Individual; Industrial fungicide; Infection; Inflammatory; Infusion procedures; Injection of therapeutic agent; innovation; Intensive Care Units; Interview; Intravenous; Length; Life; Measurement; Medical Device; Minimum Inhibitory Concentration measurement; Modeling; Monitor; Morbidity - disease rate; Mortality Vital Statistics; Mycoses; Neurologic; Neurosurgeon; neurosurgery; novel; novel therapeutic intervention; novel therapeutics; Obstruction; Opportunistic Infections; Organism; Oryctolagus cuniculus; Outcome; pathogen; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Phase; Polysaccharides; preclinical study; pressure; Procedures; Process; prototype; public health relevance; Pump; radiologist; Regimen; Research; Sampling; Serum; Site; Small Business Technology Transfer Research; Specialist; Speed (motion); Spinal; Spinal Puncture; Staging; standard of care; stem; Surface; Symptoms; System; targeted treatment; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Universities; Work

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. Early reduction in pathogen burden 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 the ability for targeted delivery of Amphotericin B (AMB) along 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 deliver the first-ever fungicidal platform. It will allow for delivery and circulation of AMB intrathecally, control of drug concentration and toxicity, rapid removal of C. neoformans and downstream mediators from the CSF, sampling of CSF to follow CFU reduction, and drainage of CSF to normalize ICP. Specific Aim 1 will understand and optimize the delivery, circulation, and dosing of AMB via the Neurapheresis system in a cranial/spinal model and develop a PK/PD model. Specific Aim 2 will demonstrate the safety and efficacy of Neurapheresis filtration and AMB circulation in a pivotal rabbit CM model study. Specific Aim 3 will complete development of the validated Neurapheresis system for intrathecal AMB delivery and targeted removal of organism from the CSF. Neurapheresis is an innovative, new therapeutic option that provides direct access to the CSF and allows for delivery and active circulation of intrathecal drug, combined with targeted pathogen removal through filtering. This treatment is complementary and does not replace standard 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 and clinical study planning 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 fungicidal approach that rapidly eliminates the CSF fungal burden and translates to reduced morbidity and mortality for CM patients worldwide.