Sickle cell disease: progress towards combination drug therapy

Abstract

Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the β^S -globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSβ⁰ thalassaemia, HbSC and HbSβ⁺ thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSβ⁰ thalassaemia, stimulated clinical trials to develop disease-specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)-approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non-chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy-HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA-approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.

Keywords: combination drug therapy; fetal haemoglobin; gene therapy; haematopoietic stem cell transplant; sickle cell anaemia; sickle cell disease.

Fig 1.

Mechanisms of fetal haemoglobin (HbF) induction by hydroxycarbamide. Shown are the various mechanisms by which hydroxycarbamide impacts the clinical symptoms of sickle cell disease. The generation of nitric oxide (NO) by hydroxycarbamide leads to sGC (soluble guanylyl cyclase) activation and subsequent cGMP-PKG signalling and p38 MAPK (mitogen-activated protein kinase) phosphorylation and repression of ERK MAPK. Once activated, p38 MAPK crosses into the nucleus and activates downstream transcription factors ATF2 and CREB1 to enhance HBG2 expression. Symbols: white circle, unmethylated cytosine. Abbreviations: ATF2, Activating Transcription Factor 2; cGMP-PKG, cyclic guanosine monophosphate-protein kinase g; CREB1, CAMP responsive element binding protein 1; ERK, extracellular signal-regulated kinase; GATA2, GATA-binding factor 2; RDR, ribonucleoside diphosphate reductase; sRBC, sickle red blood cells; WBC, white blood cell.

Fig 2.

Mechanisms of action of drugs under evaluation in human clinical trials. Shown is a summary of the major cellular, vascular and system mechanisms by which FDA-approved and other drugs improve the clinical severity of sickle cell disease. The effects have been divided into four areas/targets as shown for the sake of discussion in the text. Abbreviations: sRBC, sickle red blood cells; HbS, haemoglobin S; sGC, soluble guanylyl cyclase; PK-R, pyruvate kinase-R; PK; pyruvate kinase; TK, BCR/ABL tyrosine kinase ATP tyrosine kinase, RDR, ribonucleoside diphosphate reductase; DNMT1, DNA methyltransferase 1; DOPA, dihydroxyphenylalanine; ER, endothelial receptor; NMDA, N-Methyl-d-aspartic acid or N-Methyl-d-aspartate; P2YR, purinergic.