What is Sickle Cell Disease (SCD)?
 

Sickle Cell Disease (SCD) is an autosomal recessive disorder characterized by an abnormal molecular structure of hemoglobin. The core etiology is a point mutation in the HBB gene encoding the hemoglobin beta chain. This causes hemoglobin to polymerize abnormally under hypoxic conditions, deforming red blood cells from their normal biconcave disc shape into rigid sickle shapes. These abnormally shaped cells tend to obstruct microvessels, leading to tissue ischemia, pain, multi-organ damage, and chronic anemia due to their premature destruction, which can be life-threatening in severe cases.

The disease affects millions globally, with high incidence in Africa, the Mediterranean region, and elsewhere. Sickle cell anemia (HbSS type) is the most common form, accounting for approximately 70% of cases in people of African descent. Patients often present with recurrent pain crises, increased risk of infections, and dysfunction of various organs.
 

Pathogenesis
 

The pathological basis of sickle cell anemia (HbSS type) stems from a point mutation in the HBB gene located on the short arm of chromosome 11 (11p15.5), most commonly in the homozygous state for the βS allele (HbSS). This mutation results in the substitution of the hydrophilic glutamic acid with the hydrophobic valine at the sixth position of the β-globin chain, forming the abnormal hemoglobin tetramer HbS (α2βS2). Additionally, the βS allele can be co-inherited with other β-globin mutations (e.g., βC, βD, βO, βE) or β-thalassemia alleles, forming compound heterozygous types such as HbSC, HbSD, and HbS/β-thal, which also cause disease through similar molecular and cellular mechanisms.
 

Under low oxygen tension, HbS molecules, due to their hydrophobicity, readily polymerize, forming insoluble fibrous polymers. These polymers assemble into a rigid network within the red blood cell, forcing it to distort from the normal biconcave disc shape into a rigid sickle shape.
 

This morphological change causes red blood cells to lose their normal deformability, making it difficult for them to pass through narrow microvessels. They stagnate and obstruct blood flow in capillaries, causing local tissue ischemia and hypoxia. Concurrently, the membrane stability of sickled red cells decreases, making them more susceptible to recognition and clearance by macrophages in organs like the spleen and liver, leading to chronic hemolytic anemia.
 

During hemolysis, ruptured red cells release large amounts of free hemoglobin, which binds to and depletes nitric oxide, causing vasodilation dysfunction, endothelial damage, and vasoconstriction. Furthermore, iron ions released during hemolysis can catalyze the generation of reactive oxygen species, triggering oxidative stress, which in turn activates endothelial cells, platelets, and neutrophils, initiating sterile inflammation. In this process, inflammasomes are activated, releasing pro-inflammatory cytokines such as IL-1β and IL-18, further exacerbating vascular damage and hemolysis. Repeated stasis and reperfusion in microvessels also cause ischemia-reperfusion injury, generating a large number of oxygen free radicals upon blood flow restoration, which worsens cellular and tissue damage.
 

Image Source: Pathophysiology of Sickle Cell Disease
 

Mouse Models
 

Humanized HbS mice:​ This model involves replacing the mouse endogenous globin genes (Hba/Hbb) with human α-globin gene fragments and gene fragments containing the human βS (Glu6Val) allele, mimicking human hemoglobin composition. These mice stably exhibit red blood cell sickling, hemolytic anemia, vaso-occlusion, and multi-organ inflammation, making them a popular model for studying SCD vasculopathy and drug efficacy.
 

Advancing Gene Therapy Research
 

Gene therapy offers hope for rare diseases, but its development and validation rely heavily on animal models. Utilizing its self-developed TurboMice™ technology, MingCeler Biotech​ has developed several rare disease mouse models. The TurboMice™ technology overcomes the technical challenges of long mouse model generation cycles and low success rates for complex models. It enables editing at almost any target gene locus, allowing for the preparation of complete homozygous gene-edited mouse models directly from embryonic stem cells in as short as two months.
 

MingCeler Biotech​ can customize various SCD mouse models, such as humanized HbS mice, according to client requirements. We welcome inquiries.
 

References:

1.Sundd P, Gladwin MT, Novelli EM. Pathophysiology of Sickle Cell Disease. Annu Rev Pathol. 2019 Jan 24;14:263-292. doi: 10.1146/annurev-pathmechdis-012418-012838. Epub 2018 Oct 17. PMID: 30332562; PMCID: PMC7053558.