HbSC gets its mouse model 75 years after discovery Free

In this issue of Blood, Setayesh et al describe their mouse model of hemoglobin sickle cell (HbSC) disease, closing a critical research gap more than 75 years after HbSC was first described.¹ 

Sickle cell disease (SCD) has been on the clinical radar since 1911, when James Herrick first reported the presence of “peculiar elongated and sickle-shaped” red blood cells in a young patient from Grenada.² Nearly 4 decades later, in 1950, HbSC disease was recognized as a distinct phenotype, caused by the compound heterozygosity of hemoglobin S and another abnormal hemoglobin.³ One year later, hemoglobin C (HbC) was designated as a third form of hemoglobin---alongside hemoglobin A (normal) and hemoglobin B (HbS).⁴ 

Although homozygous sickle cell anemia (HbSS) has been the focal point of research and therapeutic development, HbSC---despite accounting for nearly one third of global SCD cases---has been consistently overlooked.⁵ The first attempt at modeling sickle hemoglobin in vivo was done with the SAD mouse in 1990, which was already quite late when compared with other monogenetic diseases (see figure).⁶ In their work, Setayesh et al have delivered a long-awaited breakthrough: the first genetically engineered mouse model that replicates the complex and understudied phenotype of HbSC disease.

Although historically labeled as a “milder” form of SCD, HbSC is anything but benign. Recent cohort studies, including the Sickle Cell Disease Implementation Consortium patient registry,⁷ have shown that people with HbSC experience significant morbidity, with higher rates of retinopathy, splenomegaly, pulmonary complications, and avascular necrosis than previously appreciated. Importantly, the pathophysiology of HbSC differs from that of HbSS, involving red cell dehydration, hemoglobin C crystallization, and increased blood viscosity---mechanisms that have remained insufficiently studied due to the absence of an animal model that accurately recapitulates the disorder.

Setayesh et al overcame this hurdle by inserting human α-globin along with 1 βS and 1 βC allele into the Townes SCD mouse background. The resulting HbSC mice exhibit hallmark features of human HbSC disease: moderate anemia, severe red blood cell dehydration, high whole-blood viscosity, and target-organ damage. Most notably, the model mimics the disproportionately high prevalence of proliferative retinopathy, a defining complication of HbSC disease.

But the authors went further. They used the model to assess the effects of hydroxyurea, a US Food and Drug Administration–approved therapy for SCD. Although hydroxyurea’s efficacy in HbSC has remained unclear---due in part to poor HbF (fetal hemoglobin) responses in clinical trials---the study provides some interesting insights. The authors show that the modest increase of HbF (up to 7%) in their model completely abrogates sickling in the oxygenscan sickling assay. This recapitulates long-standing observations in humans with HbSC. Even small reductions in HbS concentration can dramatically suppress hemoglobin polymerization and sickling.⁸ 

Moreover, hydroxyurea improved red cell deformability and reduced oxidative stress even without HbF induction, underscoring its HbF-independent effects. These improvements include lower ferryl hemoglobin levels, reduced Heinz body formation, and enhanced membrane stability. This aligns well with findings from the recent Prospective Identification of Variables as Outcomes for Treatment trial, which demonstrated that hydroxyurea conferred clinical benefit in patients with HbSC, independent of HbF levels.⁹ In this phase 2 trial, vaso-occlusive event rates were similar in patients with HbSC disease taking hydroxyurea or placebo, regardless of HbF increase.⁹ 

Last, when hydroxyurea was administered during gestation and early postnatal life---at a time when hemoglobin switching is still occurring---the authors achieved modest HbF induction in both HbSC and HbSS mice. Interestingly, HbSC mice had lower absolute HbF levels than their HbSS counterparts, despite similar F-cell frequencies. This difference parallels clinical findings and highlights the model’s translational relevance.

Of course, some caveats remain. Like many murine models of human disease, these mice exhibit a more severe erythrocyte phenotype than most patients, including elevated reticulocytosis. More importantly, for HbF regulation, the model does not include all human regulatory elements involved in hemoglobin switching. Nonetheless, the model’s ability to replicate genotype-specific clinical manifestations and therapeutic responses makes it a valuable tool for mechanistic and preclinical studies in HbSC.

Most importantly, this model underscores what clinicians and patients have long suspected: HbSC disease is not simply a milder version of HbSS---it is a distinct clinical entity with a unique pathophysiology. This distinction must be acknowledged not only in research but also in clinical trial design. Even when those with HbSC are technically permitted to enroll in trials, they are often functionally excluded due to eligibility criteria such as hemoglobin thresholds. For example, the mean hemoglobin in HbSC is ∼11.5 g/dL, yet most clinical trials impose an upper limit of 10.5 g/dL for inclusion. This effectively excludes the majority of HbSC patients from participation, further perpetuating the knowledge gap and therapeutic inequity.

The HbSC mouse model described by Setayesh et al should serve as a turning point. The model offers a robust, reproducible, and physiologically relevant platform for investigating HbSC-specific mechanisms and therapies. Just as importantly, it should serve as a call to action: to recognize HbSC as a separate disease deserving of tailored studies, dedicated interventions, and truly inclusive clinical trials.

Conflict-of-interest disclosure: E.J.v.B. has received research funding from Vertex and Agios Pharmaceuticals.