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Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1710-1719
Emerging disease-modifying therapies for sickle cell disease
1Department of Pediatrics, Division of Pediatric Hematology/Oncology, University
of North Carolina Chapel Hill School of Medicine and 2Department of Medicine, Division of Hematology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, USA
ABSTRACT
Sickle cell disease afflicts millions of people worldwide and approxi- mately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways ‘downstream’ to a point mutation in DNA, and include red blood cell membrane damage, inflamma- tion, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute’s 2014 evidence-based guideline for sickle cell disease management states that additional research is needed before investigational curative therapies will be widely available to most patients with sickle cell disease. To date, sickle cell disease has been cured by hematopoietic stem cell transplanta- tion in approximately 1,000 people, most of whom were children, and sig- nificantly ameliorated by gene therapy in a handful of subjects who have only limited follow-up thus far. During a timespan in which over 20 agents were approved for the treatment of cystic fibrosis by the Food and Drug Administration, similar approval was granted for only two drugs for sickle cell disease (hydroxyurea and L-glutamine) despite the higher prevalence of sickle cell disease. This trajectory appears to be changing, as the lack of mul- timodal agent therapy in sickle cell disease has spurred engagement among many in academia and industry who, in the last decade, have developed new drugs poised to prevent complications and alleviate suffering. Identified therapeutic strategies include fetal hemoglobin induction, inhibi- tion of intracellular HbS polymerization, inhibition of oxidant stress and inflammation, and perturbation of the activation of the endothelium and other blood components (e.g. platelets, white blood cells, coagulation pro- teins) involved in the pathophysiology of sickle cell disease. In this article, we present a crash-course review of disease-modifying approaches (minus hematopoietic stem cell transplant and gene therapy) for patients with sick- le cell disease currently, or recently, tested in clinical trials in the era follow- ing approval of hydroxyurea.
Introduction
As the most common monogenic disorder and first defined ‘molecular’ disease,1,2 sickle cell disease (SCD) comprises a complex group of hematologic disorders that share a common genetic link - a missense mutation in the seventh codon of the β- globin gene that leads to adenine being replaced with thymine (GAG→GTG). In turn, at the sixth position of the mature peptide of the β-globin protein the amino acid valine replaces glutamic acid3 which, when inherited in the homozygous state, results in erythroid precursors and mature sickle red blood cells (RBC) that contain abnormal sickle hemoglobin (HbS: a2βS2), rather than normal adult hemoglobin (HbA: a2β2). Compound heterozygous diseases (HbSC: a2βSβC; and HbSβ+ tha- lassemia: a2βSβ+-Thal) have milder features overall, but can be debilitating and highly morbid as well. Under deoxygenated conditions, HbS polymerizes intracellularly,
Marcus A. Carden1,2 and Jane Little2
Correspondence:
JANE LITTLE
jane_little@med.unc.edu
Received: April 10, 2019. Accepted: July 10, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2018.207357
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1710
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