A mouse model for hemoglobin SC disease recapitulates characteristic human pathologies.

Area of Science:

• Genetics and Genomics
• Hematology
• Disease Modeling

Background:

• Sickle cell disease (SCD) is a group of inherited blood disorders caused by mutations in the beta-globin gene (HBB).
• The most common form, HbSS, has well-established mouse models, but research on the second most common form, HbSC, is limited by a lack of suitable animal models.
• HbSC arises from distinct HBB mutations (p.Glu6Val/p.Glu6Lys) compared to HbSS (p.Glu6Val).

Purpose of the Study:

• To create and characterize a novel mouse model for HbSC, the second most prevalent form of sickle cell disease.
• To enable further investigation into the unique pathological mechanisms of HbSC disease.
• To facilitate the development of targeted therapies for HbSC.

Main Methods:

• Utilized CRISPR genome engineering to introduce HbSC mutations into the Townes mouse strain.
• The Townes strain contains human alpha- and beta-globin genes, replacing the mouse counterparts.
• Phenotypic analysis of the generated HbSC mice was performed and compared to Townes HbSS mice.

Main Results:

• Successfully generated mice carrying the HbSC alleles using CRISPR technology.
• HbSC mice displayed distinct pathological features mirroring those observed in human HbSC patients.
• These pathologies differed from those observed in the Townes HbSS mouse model.

Conclusions:

• The developed HbSC mouse model accurately recapitulates key aspects of human HbSC disease.
• This new model provides a valuable tool for studying HbSC pathophysiology and testing therapeutic interventions.
• It addresses a critical gap in animal models for SCD research, specifically for the HbSC variant.