Novel small molecule therapeutics for sickle cell disease: nitric oxide, carbon monoxide, nitrite, and apolipoprotein A-I.
A hemolysis-linked subphenotype of sickle cell disease (SCD), characterized by pulmonary hypertension, stroke, priapism and leg ulcers, is associated with decreased nitric oxide bioavailability and vasculopathy. Vasculopathy appears to have a multifactorial etiology, including mechanisms primarily that involve deficient nitric oxide (NO) signaling, but also involving altered function of NO synthase related to substrate availability and cooperating factors such as apolipoproteins. Improved understanding of the vascular pathophysiology of SCD has led to new vascular targets for translational research in SCD. This growing vascular therapeutics field in SCD is complementary to the ongoing efforts to reduce the morbidity of vaso-occlusive pain crisis. This presentation will review the current biology and translational clinical development of novel small molecules targeting sickle cell vasculopathy. Strategies targeting the hemeoxygenase-carbon monoxide pathway, the arginine-NO synthase-cGMP-phosphodiesterase 5 pathway, the nitrate-nitrite-NO pathway, and the apolipoprotein A-I pathways will be reviewed. In this context, current clinical trials of inhaled NO, CO, nitrite, sildenafil and apoA-I mimetics will be discussed.
Kato
Gregory J
GJ
Critical Care Medicine Department, Clinical Center and the Pulmonary and Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, MD 20892-1476, USA.
D000700:Analgesics / Q000627:therapeutic use; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000503:physiopathology; D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D002248:Carbon Monoxide / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D006801:Humans; D009569:Nitric Oxide / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000627:therapeutic use*; D015398:Signal Transduction
D000700:Analgesics; D016632:Apolipoprotein A-I; D065128:Endothelin Receptor Antagonists; D009573:Nitrites; D009569:Nitric Oxide; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5