Exploring Biomarkers for Sickle Cell Disease

Sickle cell disease (SCD) is a rare inherited disorder of red blood cells affecting more than 3 million people worldwide.¹ The most prevalent and severe form of SCD is sickle cell anaemia, which affects 300,000 infants each year.² Individuals diagnosed with this rare condition often endure recurrent painful episodes, heightened susceptibility to infections, and necessitate lifelong monitoring and treatment.

At the molecular level, SCD attributed to genetic mutations in the hemoglobin subunit beta (HBB) gene which encodes for β-globin – a crucial component of the oxygen-carrying protein hemoglobin. Consequently, individuals affected by SCD produce abnormal hemoglobin, causing their red blood cells (RBCs) to become hard and sticky, termed “sickle cells.” These abnormal cells have a shorter lifespan than RBCs, leading to a shortage of functioning RBCs. This has an impact on oxygen-transport around the body, which may lead to comorbidities including injury to vital organs such as the heart and brain.³

If both parents possess a faulty HBB gene, there is a 1 in 4 chance their child will have SCD.⁴ It is important to note that individuals who do not have SCD themselves can still be carriers of the condition and pass it on to their children through genetic inheritance. By identifying such carriers through diagnostic biomarkers, individuals can make well-informed decisions regarding reproductive options and take necessary measures to manage their health. Early diagnosis can also play a crucial role in enhancing outcomes and improving the quality of life for individuals living with SCD.

Since the 1950s, more than 500 biomarkers for SCD have been reported in the literature, according to Causaly data. Comparing this to more common blood diseases such as leukemia, which has over 10x more biomarkers reported, highlights the significant unmet need in the rare disease research. Two of the earliest reported biomarkers of SCD include hemoglobin SS (a gene encoding for abnormal hemoglobin) and fetal hemoglobin (component of hemoglobin in the fetus).

In the last decade (2013-2022) evidence for over 300 specific target biomarkers for SCD have been reported in the literature, according to Causaly. The biomarker with the most evidence within this criterion is abnormal hemoglobin, which has an upregulated relationship in SCD. Biomarkers with upregulated relationships with disease often play key roles in pathophysiology and thus, can serve as reliable diagnostic indicators. Therefore, we have further prioritized biomarkers for SCD by upregulated relationship type.

According to Causaly, 66 biomarkers with an upregulated relationship with SCD have been reported in the literature between 2013 and 2022. Protein PTPN1 (tyrosine-protein phosphate non-receptor type 1) was selected as an emerging biomarker of interest for SCD.⁵ PTPN1, also known as PTP1B, plays a key role in protein dephosphorylation. This is particularly significant in light of the reported observation of heightened levels of tyrosine phosphorylation in membrane proteins found in sickle cells.⁵

Recent studies have shown that PTPN1 is largely digested into lower molecular weight fragments in sickle cells compared to RBCs, and furthermore implicating PTPN1 as a contributor to symptoms of SCD.⁵ Therefore, PTPN1 may show promise as a biomarker for SCD.