Christoph Steiger

Oral drug delivery of therapeutic gases — Carbon monoxide release for gastrointestinal diseases

Deploying the therapeutic potential of carbon monoxide (CO) in various gastrointestinal diseases is challenged by inappropriate oral delivery modes. It is for this challenge, that we developed an easy to use tablet referred to as oral carbon monoxide release system (OCORS) providing precise, controlled, tunable and targeted CO delivery for the treatment of sequelae of gastrointestinal diseases. OCORS is an oral tablet based on sulfite induced CO release from the CO releasing molecule 2 (CORM-2). OCORS performance was detailed as a function of the presence of buffer within the tablet core and the composition of a semipermeable cellulose acetate coating, shielding the tablet core. OCORS delivered CO for up to 10h with a nearly linear release profile between approximately 30 to 240min. This controlled release system delivered the therapeutic gas independent of environmental pH for reliable CO generation at gastric, intestinal or colonic sites. In vivo experiments and toxicological assessments particularly with respect to observed ruthenium release of OCORS are required to demonstrate the pharmacokinetics and clinical potential of this oral delivery platform for therapeutic gases.

Prevention of colitis by controlled oral drug delivery of carbon monoxide

Carbon monoxide (CO) is an endogenous signal transmitter involved in numerous physiological processes including the gastrointestinal (GI) homeostasis. CO has been recognized as potential new therapeutic agent for motility related and inflammatory disorders of the GI tract. A therapeutic use, however, is challenged by inappropriate drug delivery modes. Here we describe a micro scale Oral Carbon Monoxide Release System (M-OCORS) designed for localized and controlled exposure of the GI tract with in situ generated CO. M-OCORS allowed for controlled release profiles lasting for several minutes or up to almost one day. These in vitro release profiles translated into a large pharmacokinetic design space following oral administration in mice and measured as CO-hemoglobin (CO-Hb) formation. M-OCORS with a release profile featuring exposure of the intestine was profiled in two independently performed studies demonstrating preventive effects in chemically induced colitis. M-OCORS significantly reduced damage scores and prevented upregulation of colitis biomarkers.

Controlled therapeutic gas delivery systems for quality-improved transplants.

Therapeutic gases enriched into perfusion solutions have been effectively used for the improvement of organ transplant quality. At present, the enrichment of perfusion solutions with gases requires complex machinery/containers and handling precautions. Alternatively, the gas is generated within the perfusion solution by supplemented carbonylated transition metal complexes with associated toxicological concerns when these metals contact the transplant. Therefore, we developed therapeutic gas releasing systems (TGRSs) allowing for the controlled generation and release of therapeutic gases (carbon monoxide and hydrogen sulfide) from otherwise hermetically sealed containers, such that the perfusion solution for the transplant is saturated with the gas but no other components from the TGRS are liberated in the solution. The release from the TGRS into the perfusion solution can be tailored as a function of the number and thickness of gas permeable membranes leading to release patterns having been linked to therapeutic success in previous trials. Furthermore, the surrogate biomarker HMGB1 was significantly downregulated in ischemic rat liver transplants perfused with enriched CO solution as compared to control. In conclusion, the TGRS allows for easy, reliable, and controlled generation and release of therapeutic gases while removing safety concerns of current approaches, thereby positively impacting the risk benefit profile of using therapeutic gases for transplant quality improvement in the future.

Localized delivery of carbon monoxide

Graphical abstract Figure. No caption available. ABSTRACT The heme oxygenase (HO)/carbon monoxide (CO) system is a physiological feedback loop orchestrating various cell‐protective effects in response to cellular stress. The therapeutic use of CO is impeded by safety challenges as a result of high CO‐Hemoglobin formation following non‐targeted, systemic administration jeopardizing successful CO therapies as of this biological barrier. Another caveat is the use of CO‐Releasing Molecules containing toxicologically critical transition metals. An emerging number of local delivery approaches addressing these issues have recently been introduced and provide exciting new starting points for translating the fascinating preclinical potential of CO into a clinical setting. This review will discuss these approaches and link to future delivery strategies aiming at establishing CO as a safe and effective medication of tomorrow.

Overcoming safety challenges in CO therapy – Extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels

ABSTRACT Carbon monoxide (CO) has demonstrated therapeutic potential in multiple inflammatory conditions including intensive care applications such as organ transplantation or sepsis. Approaches to translate these findings into future therapies, however, have been challenged by multiple hurdles including handling and toxicity issues associated with systemic CO delivery. Here, we describe a membrane‐controlled Extracorporeal Carbon Monoxide Release System (ECCORS) for easy implementation into Extracorporeal Membrane Oxygenation (ECMO) setups, which are being used to treat cardiac and respiratory diseases in various intensive care applications. Functionalities of the ECCORS were investigated in a pig model of veno‐arterial ECMO. By precisely controlling CO generation and delivery as a function of systemic carboxyhemoglobin levels, the system allows for an immediate onset of therapeutic CO‐levels while preventing CO‐toxicity. Systemic carboxyhemoglobin levels were profiled in real‐time by monitoring exhaled CO levels as well as by pulse oximetry, enabling self‐contained and automatic feedback control of CO generation within ECCORS. Machine learning based mathematical modeling was performed to increase the predictive power of this approach, laying foundation for high precision systemic CO delivery concepts of tomorrow.

Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?

Heme oxygenase (HO), the rate-limiting step in the degradation of heme to biliverdin, ferrous ion, and carbon monoxide (CO), is an ancestral protective enzyme conserved across phylogenetic domains. While HO was first described in the late 1960s and progressively characterized in the following decades, there has been a surge of innovation over the past twenty years in efforts to leverage the cytoprotective power of HO in a clinical setting. Despite the plethora of preclinical data indicating extraordinary therapeutic potential, HO has remained elusive from the physicians toolbox. The leading candidate in development, CO, has long been misconstrued as a useless toxic gas. Scientists have crafted an array of CO delivery molecules and devices to harness HO, however, each endeavor was met with limitations preventing translation into clinical practice. In this discussion, we summarize the HO / CO field with a clinical and commercial development perspective. More specifically, given the enormous global efforts and capital investment into the field, we ask: where is the breakthrough therapy?