New Therapeutic Options for the Treatment of Sickle Cell Disease

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Abstract

Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD.

New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents.

This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.

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Most cited references 106

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Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease.

Vandana Sachdev, Xunde Wang, G Kato … (2005)

Sickle cell disease is characterized by a state of nitric oxide resistance and limited bioavailability of l-arginine, the substrate for nitric oxide synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension, and patient outcomes. To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and mortality. Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed up for survival up to 49 months. Urban tertiary care center and community clinics in the United States between February 2001 and March 2005. Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants. Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality. Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in patients with secondary pulmonary hypertension. Arginase activity correlated with the arginine-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio, 2.5; 95% confidence interval [CI], 1.2-5.2; P = .006). Global arginine bioavailability, characterized by the ratio of arginine to ornithine plus citrulline, was also strongly associated with mortality (risk ratio, 3.6; 95% CI, 1.5-8.3; P<.001). Increased plasma arginase activity was correlated with increased intravascular hemolytic rate and, to a lesser extent, with markers of inflammation and soluble adhesion molecule levels. These data support a novel mechanism of disease in which hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.

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Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease

Christopher Reiter, Xunde Wang, Jose Tanus-Santos … (2002)

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The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS).

E. Rivas Plata, George Stamatopoulos, A Balassopoulou … (2010)

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/beta(0)-thal, and 165 with HbS/beta(+)-thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P = .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/HbS, HbS/beta (0)-thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients.

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Journal

Journal ID (nlm-ta): Mediterr J Hematol Infect Dis

Journal ID (iso-abbrev): Mediterr J Hematol Infect Dis

Journal ID (publisher-id): Mediterranean Journal of Hematology and Infectious Diseases

Title: Mediterranean Journal of Hematology and Infectious Diseases

Publisher: Università Cattolica del Sacro Cuore

ISSN (Electronic): 2035-3006

Publication date Collection: 2019

Publication date (Electronic): 01 January 2019

Volume: 11

Issue: 1

Electronic Location Identifier: e2019002

Affiliations

[1 ]Department of Medicine, University of Verona and AOUI Verona, Verona. Italy

Author notes

Correspondence to: Lucia De Franceschi. Department of Medicine, University of Verona and AOUI Verona, Verona; Italy. Fax: +39 045 8027473; phone: +39045 8124401. E-mail: lucia.defranceschi@ 123456univr.it

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Publisher ID: mjhid-11-1-e2019002

DOI: 10.4084/MJHID.2019.002

PMC ID: 6328043

PubMed ID: 30671208

SO-VID: 00bddf29-73be-4916-9953-b44620aee88e

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

New Therapeutic Options for the Treatment of Sickle Cell Disease

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Most cited references 106

Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease.

Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS).

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