SBIR-STTR Award

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 10,000 US cases and over 1 million cases of CM worldwide annually, with estimated deaths of 700,000 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 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 platform, that will rapidly clear specific pathogens for treating life-threatening infections of the central nervous system (CNS). The objective of the proposed project is to develop a tailored system to target and remove C. neoformans from the CSF and to evaluate its reduction in a CM animal model. Specific Aim 1 will focus on conducting in vitro testing using a design matrix tailored for Cryptococcus exclusion. Longevity and mechanical testing will be performed to ensure safety and reliability. Specific Aim 2 will evaluate the in vivo reduction of CSF fungal CFUs in a validated rabbit CM model. In summary, 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 I STTR will provide Minnetronix with the data to justify broader preclinical studies and development of a GLP-quality system for treatment of CM in Phase II. During Phase II, 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.

Public Health Relevance Statement:


Public Health Relevance:
In this Phase I STTR, Minnetronix plans to develop an innovative, new therapeutic platform for treating devastating Central Nervous System (CNS) infections. Cryptococcal meningitis (CM) occurs when a fungal pathogen (C. neoformans), invades the CNS and is seen most commonly in immunocompromised patients, such as those with HIV or post organ-transplant. CM is a deadly, infectious neurological disease that affects 10,000 people in the US and 1 million people annually worldwide, and results in a 70% mortality rate. This project will provide the first-ever localized therapy that safely targets and eliminates pathogens affecting the CNS and save lives.

NIH Spending Category:
Bioengineering; Infectious Diseases; Neurosciences

Project Terms:
Adverse effects; Affect; Amphotericin B; Animal Model; Animals; Antibiotics; Antifungal Agents; Antifungal Therapy; Area; base; Basidiomycota; Blood; Blood Circulation; Catheters; Central Nervous System Infections; Cephalic; Cerebrospinal Fluid; cerebrospinal fluid flow; Cessation of life; Chairperson; Clinical; clinical practice; Clinical Trials; Cohort Studies; Collaborations; Colony-forming units; Combined Modality Therapy; Communicable Diseases; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Custom; Data; design; Development; Device or Instrument Development; Devices; Diagnosis; Doctor of Philosophy; Drug Delivery Systems; Drug resistance; Effectiveness; Ensure; Equilibrium; Excision; Exclusion; experience; Filtration; Flucytosine; Goals; Guidelines; HIV; Hour; Immunocompromised Host; In Vitro; in vitro testing; in vivo; Inflammatory; innovation; Intensive Care Units; Intervention; Interview; Intravenous; Invaded; Life; Local Therapy; Longevity; Measurement; Mechanics; Medical Device; Modeling; Monitor; Morbidity - disease rate; Mortality Vital Statistics; nervous system disorder; Neuraxis; Neurologic; Neurosurgeon; neurosurgery; novel strategies; novel therapeutic intervention; novel therapeutics; Opportunistic Infections; Oral; Organ Transplantation; Organism; Oryctolagus cuniculus; Outcome; pathogen; Pathway interactions; Patients; Phase; preclinical study; pressure; Procedures; Process; prototype; public health relevance; Pump; radiologist; Regimen; Research; Safety; Sampling; Small Business Technology Transfer Research; Specialist; Speed (motion); Spinal; Staging; standard of care; Surface; System; Testing; Time; Translating; Universities; Work

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.

Public Health Relevance Statement:
Validation of a Novel Therapeutic Approach for Cryptococcal Meningitis PI: Lad, Shivanand and McCabe, Aaron Project Narrative In this Phase II STTR, Minnetronix plans to validate an innovative, new therapeutic platform for treating devastating central nervous system (CNS) infections. Cryptococcal meningitis (CM) occurs when a fungal pathogen (C. neoformans) invades the CNS and is seen most commonly in immunocompromised patients, such as those with HIV or post organ-transplant. CM is a deadly, infectious neurological disease that affects up to 8,000 people annually in the US, 400,000 people worldwide, and results in a 15-50% mortality rate. This project will save lives by providing the first-ever localized therapy that safely targets and directly eliminates pathogens affecting the CNS.

Project Terms:
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; cerebrospinal fluid flow; Chairperson; Clinical; Clinical Pathways; Clinical Research; Clinical Trials; Collaborations; Colony-forming units; Combined Modality Therapy; Communicable Diseases; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Custom; Data; data modeling; design; Development; Device or Instrument Development; Devices; Doctor of Philosophy; Drug resistance; Effectiveness; Ensure; Equilibrium; Excision; Exclusion; Filtration; Flucytosine; fluid flow; Future; Goals; Guidelines; Histologic; HIV; Hour; Human; human study; Immunocompromised Host; In Vitro; in vivo; Infection; Inflammatory; innovation; Instruction; Intervention; Interview; Intravenous; Invaded; Investigation; Life; Local Therapy; Measurement; Medical Device; meetings; Modeling; Morbidity - disease rate; mortality; nervous system disorder; Neuraxis; Neurologic; Neurosurgeon; neurosurgery; novel therapeutic intervention; Opportunistic Infections; Oral; Organ Transplantation; Organism; Oryctolagus cuniculus; pathogen; Patients; Phase; portability; pre-clinical; Preparation; Procedures; Process; Pump; radiologist; Regimen; Research; Sampling; Small Business Technology Transfer Research; Southeastern Asia; Specialist; Speed; Spinal; standard of care; Sterilization; System; Testing; Therapeutic; Time; Training; Translating; Universities; Validation; Work