Zeta Globin Gene Expression May Lead to Therapy for Alpha Thalassemia Major

Alpha-globin mutations are common, and the number and type of mutated alleles will determine the severity of subsequent anemia. Alpha thalassemia major (ATM) occurs with four missing or mutated genes. The condition has long been mostly fatal, but recent work with in utero transfusions has increased fetal survival.

A group of investigators from institutes and centers on several campuses of the University of California conducted a study to determine whether “the embryonic zeta-globin gene, which is expressed early in gestation prior to alpha-globin, may compensate for the lack of alpha-globin and that induction of zeta-globin after it has naturally been silenced may become a new therapy for patients with ATM.” They presented their results at the all-virtual 62nd ASH Annual Meeting & Exposition.

Using the University of California, San Francisco international registry of patients with ATM, the researchers evaluated mutations to elucidate factors related to patient survival, both with and without in utero transfusions. Then, using CRISPR-Cas9, they engineered human umbilical cord–derived erythroid progenitor (HUDEP-2) cells with the common SEA alpha-globin deletion, with zeta-globin expression preserved or deleted. Finally, they evaluated the expression of alpha- and zeta-globins.

None of the subjects who survived to birth spontaneously (n=11) had a mutation involving a deletion in zeta-globin. However, alpha-globin mutations extending into the zeta-globin gene were present in 14 of 37 patients (38%) who had been diagnosed prenatally. The researchers said this suggests that zeta-globin may play a role in fetal survival without therapy.

HUDEP-2 cells with the SEA alpha-globin deletion in which zeta-globin expression was preserved expressed higher levels of zeta-globin than wild-type cells. The researchers said this may indicate that they are a potential cell model for ATM.

They also took HUDEP-2 cells that lacked zeta-globin and applied lentivirus vectors expressing high levels of zeta-globin. This resulted in decreased expression of alpha-globin, suggesting possible reciprocal control between the genes. They also found that zeta-globin could replace missing alpha-globin.

They said their data suggest that “upregulating zeta-globin could potentially be developed to mimic the ongoing trials of using the BCL11A repressor to induce gamma-globin in patients with beta-thalassemia and sickle cell disease.”