Gene Editing for Alpha-Thalassemia

We are working on several strategies of somatic cell genome editing for hemoglobin disorders, based on our interest in alpha thalassemia major, a blood disorder for which up to 5% of the world carries a single copy mutation, yet very little is known about the fundamental molecular biology behind alpha globin regulation. A fetus possessing the four gene deletion (alpha thalassemia major, ATM) cannot produce alpha globin or the subsequent oxygen carrying molecule, hemoglobin, and therefore frequently develops severe anemia early in gestation, resulting in heart failure and death without intervention. In addition to the clinical trial of in utero HSC transplantation, we are working on various strategies to treat patients with ATM using gene therapy or gene editing. One approach is to upregulate embryonic zeta globin, which is the precursor to alpha globin and is expressed during the first trimester. We are currently working on understanding the regulation of this gene to determine whether zeta globin could be upregulated to compensate for the loss of alpha globin. Our current work investigates whether the fetal immune system is responsive against maternal alloantigens after a maternal in utero stem cell transplant. Using an in vitro mixed lymphocyte reaction, proliferative responses in CD4+ and CD8+ fetal T cells are measured after exposure to maternal antigen-presenting cells. We also collaborate with the Cromer lab at UCSF and the Kohn lab at UCLA for other strategies.