Curative vs targeted therapy for SCD: does it make more sense to address the root cause than target downstream events?

Sickle cell disease (SCD) places a heavy burden on a global and increasing population predominantly resident in resource-poor and developing countries. Progress continues to be made in preventing childhood mortality, and increasing numbers of chronically ill adults with disease are requiring care for disease sequelae. Curative therapies for SCD are therefore attractive to physicians and investigators focused on SCD. Gene therapies are being developed, and several are now in various stages of early-phase human clinical trials. However, we must also pursue avenues through which we can do the most good for the most people alive today. Such efforts include improving our understanding of disease mechanisms and which disease sequelae most strongly affect survival and interfere with quality of life. The pathways leading to disease sequelae are multiple, complex, and highly interactive. Four drugs have now been approved by the US Food and Drug Administration for SCD; however, each has a distinct mechanism and a measurable but limited effect on the many clinical sequelae of SCD. We therefore need to learn how to approach multi-agent therapy for SCD. The order of addition of each agent to treat a specific patient will need to be guided by response to previous therapy, risk factors identified for specific disease outcomes, and clinical studies to determine more comprehensively how the 4 currently approved drugs might interact and produce (or not) additive effects. Moreover, this will have to be accomplished with defined end points in mind, according to which pose the greatest threats to quality of life as well as survival.