Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso‐occlusion and nephropathy in mouse models of sickle cell disease

Abstract

Background and Purpose: Reduced nitric oxide (NO) bioavailability, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vasoocclusion, and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyzes synthesis of cyclic guanosine monophosphate (cGMP) in response to NO. cGMP amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate tumor necrosis factor alpha (TNFα)-induced inflammation in wild-type C57BL/6 mice and in "humanized" mouse models of SCD. Experimental Approach: The effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. Key Results: Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFa-induced vaso-occlusive crisis, a single dose of olinciguat attenuated leukocyte/endothelial cell interactions, improved blood flow, and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat-than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-hour urine excretion, plasma levels of cystatin C, and urinary excretion of N-acetyl-beta-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle-treated mice. Conclusion and Implications:Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion, and kidney injury in mouse models of SCD and systemic inflammation.

Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model

“…Additionally, plasma IL-6 levels, a clinically relevant biomarker of systemic inflammation (Ridker, 2016), trended lower in praliciguattreated mice, suggesting lower systemic inflammation. Praliciguat's broad anti-inflammatory effects across many tissues are likely due to its extensive tissue distribution (Tobin et al, 2018) and the previously documented anti-inflammatory effect of sGC stimulation on leukocytes (Ahluwalia et al, 2004;Tchernychev et al, 2021). These data add to the body of evidence that praliciguat has extensive anti-inflammatory activity.…”

Limitations of mouse models for sickle cell disease conferred by their human globin transgene configurations

“…Townes and Berkeley mice are valuable for examining SCD pathophysiology ( Keleku-Lukwete et al, 2015 ; Nasimuzzaman et al, 2019 ; Szczepanek et al, 2012 ) and the effects of various therapeutic perturbations, including drug treatment ( Oksenberg et al, 2016 ; Shrestha et al, 2021 ; Tchernychev et al, 2021 ; Vinchi et al, 2013 ), lentiviral vector gene transduction ( Pawliuk et al, 2001 ; Perumbeti et al, 2009 ; Pestina et al, 2009 ; Urbinati et al, 2018 ) and disruption of genes that regulate γ-to-β-globin switching, such as Bcl11a ( Xu et al, 2011 ). Additionally, the Townes mouse has been useful for studying genome-editing and base-editing approaches to alter the mutant HBB S codon ( Newby et al, 2021 ; Wilkinson et al, 2021 ).…”

Soluble guanylate cyclase stimulators and activators: new horizons in the treatment of priapism associated with sickle cell disease

“…Recently, attention has focused on the therapeutic potential of sGC stimulators and activators in this context. These compounds represent a new approach to the treatment of SCD, focusing not only on improving symptoms but also on modulating the underlying pathophysiological pathways ( Potoka et al, 2018 ; Ferreira et al, 2020 ; Sandner et al, 2021 ; Tchernychev et al, 2021 ).…”

“…This effect occurs mainly by decreasing the recruitment of leukocytes to the endothelium, thus reducing vascular occlusion ( Ferreira et al, 2020 ). Similarly, olinciguat, another sGC stimulator, was shown to reduce inflammation, vaso-occlusion, and nephropathy in a murine model for sickle cell anemia, highlighting the therapeutic potential of these compounds ( Tchernychev et al, 2021 ). Interestingly, BAY 41-2272, but not BAY 60-2770, demonstrated the ability to increase γ-globin gene expression and fetal hemoglobin production in K562 erythroleukemic cell cultures, offering an additional perspective on SCD therapy ( Ferreira et al, 2020 ).…”