Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy

Abstract

A 34-year-old African American woman with sickle cell disease and history of relatively severe hemolysis, chronic leg ulcers, and mild pulmonary hypertension presented with a new ischemic stroke. Recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of nitric oxide and its biochemical precursor L-arginine. This diminished bioavailability of nitric oxide promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase. Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including inhaled nitric oxide, sodium nitrite, L-arginine, Corresponding Author: Gregory J. Kato, MD, Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Dr, MSC 1476, Bldg 10-CRC, Room 5-5140, Bethesda, MD 20892-1476 Financial Disclosures: Dr Gladwin reports being named as a coinventor on a National Institutes of Health (NIH) government patent application for the therapeutic use of nitrite salts for cardiovascular indications and on a second patent for a hemoglobin-based blood substitute. Dr Kato reported no disclosures. Additional Information:The patient data were collected as part of a registered clinical research protocol (clinicaltrials.gov identifier NCT00081523). The patient presented in this article reviewed its contents and consented in writing to its publication. CASE PRESENTATIONThe patient is a 34-year-old African American woman with homozygous sickle cell disease (SCD) undergoing hydroxyurea therapy for several years, with an 18-year history of leg ulceration (Figure 1). Steady-state laboratory values included hemoglobin 8.7 g/dL (35th percentile for SCD patients evaluated at the National Institutes of Health [NIH] between 1999[NIH] between -2003, reticulocyte count 370×10 3 /μL (83rd percentile), and serum lactate dehydrogenase (LDH) highly elevated at 486 U/L (83rd percentile). The ratio of plasma arginine to ornithine was 0.54 (33rd percentile). The patient was found to have mild elevation of the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at 177 pg/mL, and on Doppler echocardiography, a borderline high tricuspid regurgitant jet velocity of 2.5 m/s, both suggestive of mildly elevated pulmonary systolic pressures.During a subsequent hospitalization for vaso-occlusive crisis, the patient developed clinical features of encephalopathy, renal insufficiency, and pulmonary infiltrat...

Arterial Stiffness and Stroke in Sickle Cell Disease

“…12 Our data strengthen the hypothesis of the similarities between atherosclerosis and SCD vasculopathy. 14,15 In our study, TCD was altered in 40% and AS in 90% of patients with SCD with stroke at the time of diagnosis and during the study.…”

Pulmonary Complications of Sickle Cell Disease

“…NO exerts its vascular effects principally by binding and activating soluble guanylyl cyclase, boosting intracellular cyclic guanosine monophosphate (cGMP) levels (87,88). In pulmonary vasculature, this is counterbalanced by the phosphodiesterase-5 (PDE-5) enzyme, which hydrolyzes cGMP.…”

“…In pulmonary vasculature, this is counterbalanced by the phosphodiesterase-5 (PDE-5) enzyme, which hydrolyzes cGMP. PDE-5 inhibitors delay cGMP breakdown, thereby prolonging and amplifying NO-mediated signals (87). Additionally, PDE-5 inhibitors have been shown to restore platelet activation to more normal levels in patients with SCD-PH (89).…”

“…ET-1 mediates its effects through two receptor subtypes, ET A and ET B . NO normally represses ET-1 secretion and high levels are commonly found in low NO states (87). ET-1 is present at pathologically high levels in PAH and ET receptor antagonists (ERA) are approved for PAH treatment (bosentan and ambrisentan) (87).…”

Orphan drugs for sickle vaso-occlusion: dawn of a new era of targeted treatment

“…The use of sodium nitrite as alternative source of NO has also been explored, largely by investigators at the National Institutes of Health Clinical Center. 93 The proposed mechanism involves a novel physiological function of human hemoglobin as an oxygenand pH-dependent nitrite reductase potentially converting nitrite to NO along the physiological oxygen gradient in arterial blood, accentuating vasodilation in hypoxic tissue. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methemoglobinemia or other untoward events in Phase I/II clinical trials, 94 and demonstrated dose-dependent increases in forearm blood flow.…”