The overall objective of the proposed project is to investigate the potential of the gasotransmitter carbon monoxide (CO) as an anti-inflammatory agent in Sickle Cell Disease (SCD) using a novel oral formulation of CO (HBI-002). Numerous studies, both in vitro and in vivo, demonstrate that CO has cytoprotective properties through anti-oxidant, anti-inflammatory and anti-apoptotic processes. Researchers found in three studies using four different transgenic sickle cell mouse models that the heme oxygenase-1/CO pathway is key in SCD and demonstrated that very low doses of CO are a novel approach to limiting vascular stasis and down-regulating the inflammatory process. These studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCD. Moreover, Phase 1 clinical studies of CO in both normal volunteers and SCD patients using a variety of CO delivery mechanisms have demonstrated the tolerability and safety of CO, suggesting that the very low targeted levels of COHb will not be associated with adverse outcomes. HBI-002, an oral liquid formulation, is being developed for the treatment of SCD. The oral administration of a defined dose of CO delivered by HBI-002 obviates the problems associated with previously studied inhaled or carrier-metal CO administration, enabling the potential for the necessary chronic, safe, non-toxic outpatient dosing of CO. HBI-002 comprises CO in a water-based solution of proprietary excipients to maximize CO content. Proof-of-concept manufacture of HBI-002 has been demonstrated. Pharmacokinetic and pharmacodynamic studies in rats and in two adult healthy volunteers have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that CO delivered from HBI-002 improves outcomes in an appropriate SCD animal model and to determine the minimum effective dose in SCD mice to inform dosing in planned clinical trials.
Public Health Relevance Statement: Public Health Relevance: This application aims to determine whether, and the dose at which, HBI-002, an oral carbon monoxide (CO) therapeutic, improves outcomes in an animal model of Sickle Cell Disease (SCD). HBI-002 represents an innovative means of delivering the gasotransmitter CO that has the potential for chronic, safe, non-toxic in-home use, with exact dosage in contrast to the currently available means of CO delivery. If successful, the proposed project will provide critical proof-of-concept and dosing information for further development of HBI- 002 in SCD, with the ultimate objective being to provide a therapeutic to reduce the incidence of vaso-occlusive crises and inflammation and thus reduce the incidence of disability and premature mortality in this devastating disease.
NIH Spending Category: Hematology; Orphan Drug; Prevention; Rare Diseases; Sickle Cell Disease
Project Terms: Adult; adverse outcome; Animal Model; Anti-inflammatory; Anti-Inflammatory Agents; Antioxidants; Apoptotic; base; Binding; Biological Availability; Blood Vessels; Breathing; Carbon Monoxide; Cell Adhesion Molecules; Cells; Cerebrum; Characteristics; Chronic; Clinical Research; Clinical Trials; cost; Data; Development; disability; Disease; Disease model; disorder prevention; dosage; Dose; Drug Kinetics; Excipients; experience; Feedback; Formulation; Grant; healthy volunteer; heme oxygenase-1; Hemoglobin; Home environment; Human Volunteers; Hypoxia; improved outcome; In Vitro; in vitro testing; in vivo; Incidence; Individual; Inflammation; Inflammatory; Injury; innovation; Life; Life Expectancy; liquid formulation; Medical; Metals; Methods; Modeling; Morbidity - disease rate; mouse model; Mus; neuroprotection; novel; novel strategies; Oral; Oral Administration; Organ; Orphan; Outpatients; Pain; Pathway interactions; Patients; Peripheral; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenotype; pre-clinical; Preclinical Testing; Premature Mortality; prevent; Prevention; Process; Property; Proteins; public health relevance; Quality of life; Rattus; Regimen; Research; research clinical testing; Research Personnel; respiratory; response; Role; Safety; Seasons; Sickle Cell; Sickle Cell Anemia; Staging; Testing; Therapeutic; therapeutic development; Therapeutic Effect; Toxic effect; Toxicology; Transgenic Organisms; Venous; volunteer; Water
