Oral Carbon Monoxide Therapeutic to Prevent Vaso Occlusive Crises in Sickle Cell Disease

DESCRIPTION provided by applicant 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 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 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 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 an oral liquid formulation is being developed for the treatment of SCD The oral administration of a defined dose of CO delivered by HBI 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 comprises CO in a water based solution of proprietary excipients to maximize CO content Proof of concept manufacture of HBI 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 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 This application aims to determine whether and the dose at which HBI an oral carbon monoxide CO therapeutic improves outcomes in an animal model of Sickle Cell Disease SCD HBI 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 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