Page 195 - 2022_02-Haematologica-web

Sulfated non-anticoagulant heparin in SCD treatment
Figure 4. S-NACH treatment regulates the levels of inflammatory mediators. Total plasma from sickle cell disease (SCD) mice that were untreated, treated with sul- fated non-anticoagulant heparin derivative (S-NACH; 10 mg/kg) or treated with 5-hydroxymethyl-2-furfural (5-MF) was harvested and frozen. Cytokines in blood plas- ma were measured in triplicate. S-NACH treatment significantly changed the plasma levels of the analytes (*P<0.0005). For most analytes, the effects of 5-HMF were comparable to those of S-NACH at 6 h. SD: standard deviation; IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; MCP-1: monocyte chemoattractant protein 1; M-CSF: monocyte colony-stimulating factor; VEGF: vascular endothelial growth factor
thase expression. The protective effects of S-NACH treat- ment were associated with reductions of the basal expres- sion of the two isoforms of arginase, ARG1 and ARG2, in lung epithelial cells.44
In another previous study, we measured the different biomarkers of inflammation in patients with SCD (35 patients with painful crises and 30 patients in steady state) in and 35 healthy donors. Plasma levels of several chemokines and cytokines including TNF-a, IL-1b, IL-6, IL-8, MCP-1, macrophage inflammatory protein 1a (MIP1a), and IFN-g in patients with SCD were distinctly and statistically significantly higher during painful crises and at steady state than in healthy donors (2- to 10-fold increases).45
The observed anti-sickling properties are in concor- dance with our expectations when compared to those produced by GBT440 (voxelotor, Oxybryta), which was recently approved for use by the Food and Drug Administration. There are some concerns that oxygen affinity-shifting strategies may be associated with differ- ent cerebrovascular risks,46 although this was adequately addressed by Estepp.47 Nonetheless, definitive reports on long-term use will provide conclusive information on this issue. With this in mind, our multimodal approach also incorporates polyanionic glycosaminoglycans such as heparins, which can be introduced into sickle RBC HbS by synthetic lipid vesicles. Once introduced, they would block sickling and also modulate ATPase activity and the charge of the RBC membrane in hypoxia.48 SCD occurs due to the replacement of an acidic, hydrophilic amino
acid (glutamic acid) in position 6 of the b chain of Hb with a non-polar, hydrophobic valine amino acid and this change causes a disturbance in Hb structure. We therefore speculate that S-NACH (polyanionic glycosaminoglycan) may reverse the polarity to make the HbS more soluble. This mechanism of action remains under investigation.
We further speculate that S-NACH antagonizes hep- cidin and might provide additional benefits in SCD by improving iron hemostasis, as suggested in a recent report.49 Additionally, our findings demonstrate that S-NACH plays a role similar to that of the non-anticoagu- lant heparin fractions from enoxaparin, which were shown to have an effect on inflammatory mediators.26,50 Furthermore, our thromboelastography assay results with S-NACH did not show any changes in platelet functions (data not shown). Indeed, S-NACH retains all the multi- modal actions of the low molecular weight heparin tinza- parin but without systemic anticoagulation and its associ- ated bleeding side effects. Tinzaparin demonstrated signif- icant effects on the resolution of acute pain crises in patients with SCD in double-blind, randomized clinical trials.51
Overall, the effects of S-NACH on RBC sickling mor- phology, RBC adhesion, and regulation of inflammation resulted in increased survival of SCD mice under hypoxia. This study serves as a proof-of-concept that S-NACH is safe with respect to bleeding tendencies and argues for further detailed safety and efficacy studies in preclinical models of toxicity, the results of which would help guide and inform future human studies.
haematologica | 2022; 107(2)
537