New insights into sickle cell disease: mechanisms and investigational therapies

Abstract

Purpose of review: Sickle cell disease (SCD) afflicts millions worldwide. The simplicity of its single nucleotide mutation belies the biological and psychosocial complexity of the disease. Despite only a single approved drug specifically for the treatment of SCD, new findings reviewed from 2015 provide the direction forward.

Recent findings: The last year has provided a wealth of support for mechanisms affecting the red cell, hemolysis and vasculopathy, the innate immune system activation, blood cell and endothelial adhesiveness, central sensitization to pain, and chronic brain injury. The evidence supporting expanded use of hydroxyurea continues to mount. Many promising therapies are reaching clinical trial, including curative therapies, with more on the horizon.

Summary: Evidence is compelling that the use of hydroxyurea must be expanded by clinicians to gain the full pleiotropic benefits of this approved drug. Clinicians must become aware that severe acute and chronic pain has a biological and neurologic basis, and the understanding of this basis is growing. Researchers are testing investigational therapies at an unprecedented pace in SCD, and partnership between patients, researchers, and the private sector provides the most rapid and productive way forward.

Figure 1. Publications each year involving sickle cell

This graph represents the annual publication rate of articles found on PubMed with the search term “sickle,” averaging 391 per year between 1980 and 2000. During the last 15 years, the publication number has increased by an average of 51 publications each year, rising from approximately 400 to nearly 1200 per year.

Figure 2. Key Insights from 2015 Involving Sickling, Thrombosis and Vasculopathy

Dark boxes include altered physiology in SCD, gray boxes include altered outcomes, and white boxes include current attempted therapeutic interventions being described in patients or mouse models. This figure summarizes highlights from new evidence published in 2015 and is not comprehensive. NO, nitric oxide; HbF, fetal hemoglobin; apoL-I, apolipoprotein L-I; HO-1, heme oxygenase-1; IVIG, intravenous immunoglobulin G.

Figure 3. Key Insights from 2015 Involving the Brain and Pain

Dark boxes include altered physiology in SCD, gray boxes include altered outcomes, and white boxes include current attempted therapeutic interventions being described in patients or mouse models. This figure summarizes highlights from new evidence published in 2015 and is not comprehensive. MRI, magnetic resonance imaging; JNK, c-Jun N-terminal kinase; ERK, p44/p42 extracellular signaling-regulated kinase; p38, mitogen-activated protein kinase.