Therapeutic strategies for sickle cell disease: towards a multi-agent approach

Abstract

For over 100 years, clinicians and scientists have been unraveling the consequences of the A to T substitution in the beta globin gene that produces hemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anemia, hemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of hemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD — hydroxyurea and L-glutamine — are approved by the US Food and Drug Administration. Moreover, these treatment options do not fully address the manifestations of SCD. The pathophysiology of SCD suggests a complex network of interdependent processes, and in this article, we review efforts to develop new drugs targeting these processes, including agents that reactivate fetal hemoglobin, anti-sickling agents, anti-adhesive agents, modulators of inflammation, ischemia/reperfusion and oxidative stress, anti-thrombotics, anti-platelet agents and agents that counteract free hemoglobin/heme. We also discuss gene therapy, which holds promise of a cure, although its widespread application is currently limited by technical challenges and the expense of treatment. We thus propose that developing systems-oriented multi-agent strategies based on SCD pathophysiology is needed to improve to improve the quality of life and survival of people with SCD.

Hemoglobin S polymerization and sickle cell disease: A retrospective on the occasion of the 70th anniversary of Pauling's Science paper

“…There are dramatic advances in curing sickle cell disease by hematopoetic stem cell transplantation, 64 with gene therapy cures in the near future. 65,66 However, these treatments are expensive and require advanced medical facilities and are therefore not available to the vast majority of patients in the world suffering from sickle cell disease and may not be for decades. Consequently, what is urgently needed now is an inexpensive anti-sickling pill.…”

The molecular basis for the prothrombotic state in sickle cell disease

“…For a more comprehensive overview of arterial thrombosis and/or SCD management, the reader is referred to recent publications in the literature. 1,[11][12][13]…”

Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease

“…However, a patient with two sickle genes are named to have the HbSS form of SCD, while a patient who inherits one S gene and another abnormal hemoglobin gene (C, beta thalassemia, D, E, or O) will have alternate types of SCD such as HbSC or HbS beta thalassemia. Patients with SCD represent a significant health care burden in terms of cost, and despite a number of therapeutic strategies, life expectancy in this population remains decades premature compared to that of the general population (3)(4)(5). As the most commonly inherited blood disease, SCD affects >100,000 in the United States and millions more worldwide (6).…”