Search

Summary: The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS‐oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half‐life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once‐daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601. [ABSTRACT FROM AUTHOR]

Background: Hemoglobin (Hb)‐based oxygen (O2) carriers (HBOCs) are being developed as alternatives to red blood cells and blood when these products are unavailable. Clinical trials of previous HBOC generations revealed side effects, including hypertension and vasoconstriction, that were not observed in preclinical studies. Large molecular weight (MW) polymerized bovine Hb (PolybHb) represents a new class of HBOC with promising results. We evaluated the safety profile of PolybHb after an exchange transfusion (ET) in guinea pigs (GPs). This study compares changes in indices of cardiac, inflammatory, and organ function after ET with high (R‐state) and low (T‐state) O2 affinity PolybHb with high MW. Study Design and Methods: Guinea pigs underwent a 20% ET with PolybHb. To assess the implication of PolybHb ET on the microcirculation, hamsters instrumented with a dorsal window chamber were subjected to a similar volume ET. Results: T and R‐state PolybHb did not induce significant alterations in cardiac function. T‐state PolybHb induced mild vasoconstriction shortly after transfusion, while R‐state did not have acute effects on microvascular tone. Conclusion: Large MW PolybHbs were found to be safe and efficacious in increasing O2 carrying capacity and the O2 affinity of the PolybHb did not affect O2 delivery or extraction by tissues in relevant preclinical models. In conclusion, these results suggest that both T‐state and R‐state PolybHb are safe and do not impair O2 delivery. The results are encouraging and support further evaluation of high MW PolybHbs and their future feasibility compared to allogenic blood in a trauma model. [ABSTRACT FROM AUTHOR]

R4206 --> 689.6 --> Hemoglobin (Hb)‐based O2 carriers (HBOC) are being developed as alternatives to blood. Large molecular weight polymerized human Hb (PolyhHb) represents a new class of HBOC with promising results. It has been shown that PolyhHb can be locked in the T‐state (low O2 affinity) or R‐state (high O2 affinity) to control and target O2 delivery and avoid damage. The present study hypothesized that PolyhHb's quaternary state could differently affect safety and hemodynamics restoration, by controlling O2 distribution. Thus, we aimed to compare PolyhHb T‐state and R‐state to restore hemodynamics after trauma, and toxicity 24 hrs after resuscitation. To test the efficacy to restore hemodynamics, Wistar rats were instrumented with catheters in the femoral artery and vein, and subjected to TBI through a pneumatic controlled cortical impact. Hemorrhagic Shock (HS) was induced by blood withdrawal to achieve a mean arterial pressure (MAP) between 35‐40mmHg, and the hypotensive state was maintained for 90 min. Animals were separated into 3 groups based on the resuscitation solution: Blood, PolyhHb T‐state, or R‐state and, followed for 2 hrs after resuscitation. For toxicity evaluation guinea pigs (GP) (a more clinically relevant model due to lack of ascorbic acid production) were anesthetized and the carotid artery and jugular vein were catheterized, HS was induced by 40 % blood volume (BV) withdrawal, and the hypovolemic state was maintained for 50 min. GP was divided into 2 groups, and 25% of their BV was reinfused with PolyhHb T‐state or R‐state. Rats resuscitated with Blood and T‐state had a higher increase in MAP 30 min after resuscitation when compared to R‐state. Showing higher efficacy of T‐state to restore hemodynamics compared to R‐state. The T‐state group showed lower O2 saturation 30 min after reperfusion compared to R‐state and Blood groups. However, 2 hrs after resuscitation both the Blood and T‐state groups presented lower O2 saturation compared to R‐state. Resuscitation with R‐state in the GP increased AST, ALT, and liver chemokine ligand‐1 (CXCL1) (markers of liver damage and inflammation), suggesting that R‐state caused greater liver damage compared to T‐state. It was also observed an increase in the BUN, urine NGAL, and serum creatinine in the R‐state group compared to the T‐state group, showing an increased kidney injury in the animals resuscitated with R‐State PolyhHb. Also was observed higher levels of serum Il‐6, CXCL‐1, and Il‐10, in the R‐state group compared to the T‐State group, showing elevated inflammation in this group. Finally, was observed by increased levels of cardiac IL‐6, tumor necrosis factor‐alpha, monocyte chemoattractant protein‐1, troponin, and c‐reactive protein, higher cardiac damage in the R‐sate group when compared to the T‐state group. Our results showed that T‐state has higher efficacy on restoring hemodynamics in a model of TBI followed by HS, and also presented reduced vital organs toxicity in GP, when compared to R‐state. These results are promising and encourage the use of this new generation of PolyhHb T‐state as an alternative when blood is not available. [ABSTRACT FROM AUTHOR]