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

Abstract

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 physician's 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?

Antioxidative Effects of Thymus quinquecostatus CELAK through Mitochondrial Biogenesis Improvement in RAW 264.7 Macrophages

“…We first performed immunostaining to confirm the location of HO-1 in RAW 264.7 macrophages, as shown in Supplementary Figure S2A . Previous studies have shown that HO-1 localizes to several compartments within the cell, including the mitochondria [ 22 ]. Double staining with the mitochondria-specific marker MitoTracker indicated that HO-1 localized to the cytoplasm of macrophages.…”

The HO-1-expressing bone mesenchymal stem cells protects intestine from ischemia and reperfusion injury

“…HO-1, a 32 kDa enzyme containing 288 amino acid residues, is a stress-induced isoform present throughout the body. HO-1 has been reported in the mitochondria, cell nucleus, and plasma membrane [21]. HO-1 can attenuate oxidative damage and protect the myocardial, neurological and renal I/R injury in previous research and the expression of HO-1 in response to different inflammatory mediators may contribute to the resolution of inflammation and has protective effects against oxidative injury [22, 23].…”

Adaptive Potential of the Heme Oxygenase/Carbon Monoxide Pathway During Hypoxia

“…Induction of HO-1 or exposure to CO offer dose-dependent anti-inflammatory and cytoprotective effects ( Otterbein et al, 2016 ). The cytoprotective effects of CO were first demonstrated in acute lung injury, and these findings rapidly expanded through the work of numerous laboratories to most models of acute organ injury ( Hopper et al, 2018 ). Administration of exogenous CO or higher HO-1 activity increases the expression of anti-inflammatory cytokines and reduces expression of multiple pro-inflammatory cytokines during acute pulmonary inflammation ( Konrad et al, 2016 ; Zhang et al, 2019 ).…”