Multi-omics Helps Reveal How Sickle Cell Disease and Beta-Thalassemia Advance

Research study background

Sickle cell disease (SCD) and beta thalassemia (β-thal), the most common chronic inherited hemolytic disorders, are caused by mutations in the hemoglobin beta subunit (HBB) gene and affect millions of children and adults worldwide. In SCD, a single amino acid change in the HBB gene leads to the formation of sickle hemoglobin. In β-thal, HBB gene mutations reduce beta-globin production, which causes the accumulation of alpha-globin. In both SCD and β-thal, there is premature hemolysis (destruction of red blood cells) primarily within the liver and spleen which can lead to liver cirrhosis, hypersplenism and anemia. Despite these common comorbidities, their disease progression is clinically and physiologically different.

In this study, investigators sought to better understand the metabolism and protein composition of liver and spleen tissues of SCD and β-thal. This work is part of an ongoing partnership between the Center for Cancer and Blood Disorders at Children’s Hospital Colorado and the University of Colorado Anschutz Medical Campus for pediatric and adult hemolytic disorders research and clinical care.

The team evaluated age and sex-matched SCD, β-thal and control mouse models using a muti-omics approach to highlight metabolic and proteomic differences in the spleen and liver. They observed similar antioxidant and immunosuppressive characteristics within the spleens of the SCD and β-thal models, indicating a shared response to oxidative stress. The SCD model spleens shifted toward purine metabolism and reduced glycolysis, while the β-thal model spleens did not, indicating variations in response to red blood cell damage.

“In the beta-thalassemia mice, the spleens adapted to be less energy efficient to counteract the oxidative damage which occurs from abnormal hemoglobin,” says Christina Lisk, PhD, a post-doctoral research fellow at CU Anschutz and contributing study author.

SCD model livers developed a distinct a pro-inflammatory phenotype, a characteristic that was not shared by the β-thal model livers. This suggests that in each disease, the liver has a profoundly different response to hemolytic stress.

Relevance to future research

Data from this study provides key insights into the severity of hemolysis, how these diseases advance and their impact on organ function. These observed differences in how energy and protein are processed in the livers and spleens in mouse models of SCD and β-thal may help inform the development of targeted treatments.

Currently, the team is evaluating four novel therapeutics in animal models of SCD. These treatments involve removing and detoxifying hemoglobin and two of its breakdown products, heme and iron, from the bloodstream and tissues. The fourth is targeting a subset of macrophages, the type of immune cell that defends against infections and helps maintain tissue homeostasis.