Many diseases respond to CO therapy


Work with CO and more recently with CORMs in tissue culture and in animals revealed the therapeutic potential of CO for a variety of diseases. Thus, it has been observed that CO relaxes blood vessels and exerts anti-thrombotic effects by inhibiting platelet aggregation and derepressing fibrinolysis. In addition CO reduces ischemia/reperfusion injury and inflammatory responses. Finally CO inhibits apoptosis of endothelial and epithelial cells and reduces proliferation of smooth muscle cells, fibroblasts and T lymphocytes. At the molecular level, CO interacts with and/or modulates the function of a number of proteins that are validated targets for known drugs, or drugs under development, such as soluble guanylyl cyclase, high conductance calcium sensitive K+ channels, and mitogen activated protein kinases (MAPKs). CO also inhibits the production of cytokines such as TNF, IL-1, IL-6, and endothelin, which are implicated in the pathology of a variety of diseases.

Beneficial effects of CO inhalation have been demonstrated in animal disease models mainly by the research groups of Leo Otterbein at Harvard Medical School in Boston and Augustine Choi at Pittsburgh University Medical School and their collaborators, but also by a few independent research groups. Inhalation of CO at doses between 10 and 1000 ppm (in most cases 250 ppm) protected animals against septic shock, hemorrhagic shock, restenosis after arterial balloon injury, pulmonary hypertension, lung and heart injury caused by ischemia/reperfusion, lung injury caused by hyperoxia or ventilation, bleomycin-induced lung fibrosis, bronchoconstriction, TNF/galactosamine and acetaminophen induced hepatitis, necrotizing enterocolitis of neonates, inflammatory bowel disease in IL-10 deficient mice, and postoperative ileus in mice, rats and pigs. Inhahation of CO also protects against ischemia/reperfusion injury of organ and cell transplants, transplant atherosclerosis and prolongs survival of xenogeneic and allogeneic heart and kidney transplants.

The therapeutic potential of CORMs has been demonstrated in a few studies. A CORM developed by Roberto Motterlini and colleagues at the Northwick Park Institute for Medical Research reduced the size of infarcts caused by ischemia/reperfusion injury of the heart, protected rodents against ischemia and cisplatin-induced renal failure, and prolonged allograft rejection. Methylene chloride, a compound developed by Sangstat Medical Corporation, Fremont, CA, as a cytochrome P450 dependent CO-donor, reduced transplant atherosclerosis in allogeneic aorta grafts in rats. The compound also protected rats against experimentally induced arthritis and autoimmune encephalitis and protected mice against lipopolysaccheride induced liver injury.
On the basis of these pre-clinical studies inhalation of CO and CORMs represent promising, novel approaches to the treatment of a variety of diseases such as hemorrhagic shock, pulmonary hypertension, arterial restenosis, conditions involving acute inflammatory responses to tissue injury by ischemia/reperfusion (myocardial infarction, stroke, transplantation), microbial (LPS) and other toxins (cisplatin acetaminophen), and conditions involving chronic inflammatory responses (rheumatoid arthritis, asthma, colitis, atherosclerosis).

ALFAMA develops CORMs for both acute and chronic diseases. With regard to the latter ALFAMAhas chosen rheumatoid arthritis as a preferential target mainly because of the well established ability of CO to inhibit TNF production and the proven clinical efficacy of TNF neutralizing, recombinant proteins such as infliximab or etanercept. ALFAMA is currently evaluating CORMs in rodent arthritis models and, in addition, in several acute disease models.