Allosteric control of hemoglobin S fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease

Abstract

<jats:p>The pathology of sickle cell disease is caused by polymerization of the abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal hemoglobin has been replaced by adult hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of hemoglobin S with pancellular hereditary persistence of fetal hemoglobin are both relatively benign conditions.</jats:p>

Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease locus in xenograft mouse and non-human primate models

“… 27 The E7 deletion (GAG) may be enhanced up to detectable levels by microhomology in the rhesus β-globin gene (GAGGAG). Indels in the βs-globin gene can reduce pathogenic HbS production, allowing one to prevent the sickling of RBCs; 28 thus, they should contribute positively to SCD gene correction therapy. This high-efficiency gene editing method would allow for therapeutic-level gene correction in SCD CD34 + cells assessed in vitro .…”

Oxidation of Erythrocytes Enhance the Production of Reactive Species in the Presence of Artemisinins

“…The same phenomenon is described in pro-oxidant mutations, such as SCD, where accelerated denaturation of Hemoglobin S hemichrome formation and release of heme may collectively induce oxidative stress within the RBC. Antioxidant compounds have been produced in order to prevent oxidative stress presenting antisickling effects [ 7 , 8 , 42 ].…”

A Small Key for a Heavy Door: Genetic Therapies for the Treatment of Hemoglobinopathies

“…Interestingly, the most important ameliorating effect of fetal globin on the SCD phenotype is its enhanced oxygen affinity which leads to increased oxygen tension in the RBCs carrying HbS. This prevents sickling as low intracellular oxygen levels are usually required for pathologic HbS polymerization to occur (Henry et al, 2020 ). Indeed, for instance, polymorphisms in important ɤ-globin-regulating loci (e.g., BCL11A and HBS1L - MYB ) leading to ɤ-globin persistence into adulthood can ameliorate the clinical severity of SCD (Lettre et al, 2008 ; Creary et al, 2009 ; Makani et al, 2011 ; Sokolova et al, 2019 ).…”