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Ferrata Storti Foundation
Targeting sickle cell disease root-cause pathophysiology with small molecules
Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
ABSTRACT
The complex, frequently devastating, multi-organ pathophysiology of sickle cell disease has a single root cause: polymerization of deoxy- genated sickle hemoglobin. A logical approach to disease modifica- tion is, therefore, to interdict this root cause. Ideally, such interdiction would utilize small molecules that are practical and accessible for world- wide application. Two types of such small molecule strategies are actively being evaluated in the clinic. The first strategy intends to shift red blood cell precursor hemoglobin manufacturing away from sickle hemoglobin and towards fetal hemoglobin, which inhibits sickle hemoglobin polymeriza- tion by a number of mechanisms. The second strategy intends to chemical- ly modify sickle hemoglobin directly in order to inhibit its polymerization. Important lessons have been learnt from the pre-clinical and clinical evalu- ations to date. Open questions remain, but this review summarizes the valuable experience and knowledge already gained, which can guide ongo- ing and future efforts for molecular mechanism-based, practical and acces- sible disease modification of sickle cell disease.
Introduction
Sickle cell disease (SCD) demands practical, accessible oral therapies, since it is a problem of global scope. It afflicts millions of people worldwide, and has an espe- cially high prevalence in pediatric populations in low-income, malaria-belt coun- tries.1 Such therapies are technically plausible, since despite the complex and poten- tially devastating multi-organ pathophysiology of SCD, this condition has a single, well-characterized root cause: polymerization of deoxygenated sickle hemoglobin (HbS). The hemoglobin molecule is an assembly of two a-like protein subunits and two β-like protein subunits (a2β2), each with a heme moiety to transport an oxygen molecule. In SCD, the gene for the β sub-unit (HBB) of adult hemoglobin (HbA) contains an ‘A’ to ‘T’ mutation in the seventh codon. The β sub-units (βS) produced by this mutated gene substitute a hydrophilic glutamate with a hydrophobic valine, predisposing deoxygenated HbS (a2βS2) to polymerization and gelation in red blood cells (RBC). This affects RBC viability, rheology and adhesiveness, pro- moting hemolysis, endothelial damage, occlusion of small blood vessels, and thromboses of large vessels. The hemolytic anemia is frequently severe, and is only partially and non-sustainably compensated by >10-fold increases in erythropoiesis.2 The net consequence of this anemia and vaso-occlusion is decreased oxygen delivery and hypoxic injury to potentially all tissues of the body, manifest clinically as episodic pain, chronic pain, avascular necrosis of bones, infec- tions, overt and silent strokes, renal/respiratory/cardiac/hepatic failure, and early death. In the USA >$1 billion in annual health care costs is attributed to SCD, and even so, the median life expectancy of affected individuals is shortened by two or more decades on average.3,4 Most children with SCD in low-income countries do not even survive to adulthood.1 By way of emphasis, all this morbidity and mortal- ity begins with a single process, polymerization of deoxygenated HbS in RBC, and it is therefore logical to attempt to interdict this root cause. Two major small mol- ecule drug approaches are in active clinical evaluation: (i) small molecules to shift the hemoglobin manufactured by RBC precursors from HbS to fetal hemoglobin (HbF), and (ii) small molecules to chemically modify HbS to impede its polymer-
Yogen Saunthararajah
Haematologica 2019 Volume 104(9):1720-1730
Correspondence:
YOGEN SAUNTHARARAJAH
saunthy@ccf.org
Received: May 10, 2019. Accepted: July 9, 2019. Pre-published: August 8, 2019.
doi:10.3324/haematol.2018.207530
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1720
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