Scientists Try New Approach to Sickle Cell Disease

Hematologists have long sought to reactivate fetal hemoglobin as a treatment for children and adults with sickle cell disease (SCD), a painful, sometimes life-threatening genetic disorder that deforms red blood cells and disrupts normal circulation.

Shortly after birth, regulatory elements in DNA shift the body from producing the fetal form of hemoglobin to producing the adult form instead. But when patients with SCD undergo this transition, their inherited gene mutation distorts adult hemoglobin, forcing red blood cells to assume a sickle shape.

Hematology researcher at Children's Hospital Jeremy W. Rupon, MD, PhD, who worked in collaboration with a former postdoctoral fellow, Wulan Deng, PhD, in the laboratory of Gerd Blobel, MD, PhD , reprogrammed gene expression to reverse the biological switch. This caused cells to resume producing fetal hemoglobin, which is not affected by the SCD mutation, and produces normally shaped red blood cells.

"Our study shows the power of a technique called forced chromatin looping in reprogramming gene expression in blood-forming cells," Dr. Rupon said. "If we can translate this approach to humans, we may enable new treatment options for patients."

Dr. Blobel's team demonstrated in previous work that chromatin looping, a tightly regulated interaction between widely separated DNA sequences, drives gene transcription - the conversion of DNA code into RNA messages to carry out biological processes.

In the current study, the researchers custom-designed a genetically engineered zinc finger protein that latched onto a specific DNA site carrying the code for fetal hemoglobin. They attached the zinc finger to another protein that forced a chromatin loop to form. The loop then activated gene expression that produced embryonic hemoglobin in blood-forming cells from adult mice. The team obtained similar results in human adult red blood cells, forcing the cells to produce fetal hemoglobin.

Dr. Rupon presented the study team's findings during the American Society of Hematology annual meeting in New Orleans.