Novel Small Molecule Therapeutics for Sickle Cell Disease: Nitric Oxide, Carbon Monoxide, Nitrite, and Apolipoprotein A-I

Abstract

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 heme-oxygenase-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.

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

“…52 Insight into the pathogenesis of sickle vasculopathy many guide future therapies and has broad applications for other hemolytic anemias. Some interventions that might improve vasculopathy in hemoglobinopathies are listed in Table 1, while novel therapeutic strategies are discussed in depth in an accompanying article by Dr. Gregory Kato, 88 beginning on page 186. Combination therapies that target hemolysis and oxidative stress should be considered in future studies.…”

Stroke in patients with sickle cell disease

“…In mouse models, supplementation with arginine has been shown to decrease hemolytic rate and NO scavenging [136]. Unfortunately, results of human studies remain inconclusive [137,138]. Statins, which increase NO and decrease leukocyte adhesion, are also being studied [139].…”

Pulmonary Complications of Sickle Cell Disease

“…A study of 10 patients with SCD reported that oral arginine (0.1 g/kg) produced a 15.2% mean reduction in estimated PASP from 63.9 (13) mm Hg to 54.2 (12) mm Hg (P ¼ 0.002) after 5 days of therapy (97). In another study of adults on hydroxyurea, addition of highdose arginine for 3 months doubled the plasma arginine levels (47 6 16 to 96 6 58 mM, n ¼ 8, P , 0.005) but did not change the TRV (2.57 6 0.32 to 2.72 6 0.40 m/s, n ¼ 9, P ¼ not significant) (95). It is not clear whether in this trial hydroxyurea may have obscured beneficial effects of arginine supplementation on TRV or hematologic parameters.…”

“…Ordinarily, L-arginine is converted by NO synthase to citrulline plus NO (95). Arginine dysregulation has been associated with reduced NO bioavailability and some SCD complications.…”

“…The true efficacy and potential adverse effects of long-term very high dose arginine have not been examined adequately, and right heart catheterization end points have not been evaluated. Although it is available as a dietary supplement without a prescription, providers and patients should be cautious about adopting it until more research is completed (95).…”