January 2014

Flipping Gene Switch Could Lead to Sickle Cell Disease Treatment


Hematology researchers at Children’s Hospital have manipulated key biological events in adult blood cells to produce a form of hemoglobin normally absent after the newborn period. Because this fetal hemoglobin is unaffected by the genetic defect in sickle cell disease (SCD), the cell culture findings may open the door to a new therapy for the debilitating blood disorder.

“Our study shows the power of a technique called forced chromatin looping in reprogramming gene expression in blood-forming cells,” said hematology researcher Jeremy W. Rupon, MD, PhD. “If we can translate this approach to humans, we may enable new treatment options for patients.”

Dr. Rupon presented the study team’s findings during the American Society of Hematology (ASH) annual meeting in New Orleans. Dr. Rupon worked in collaboration with a former postdoctoral fellow, Wulan Deng, PhD, in the laboratory of Gerd Blobel, MD, PhD.

Hematologists have long sought to reactivate fetal hemoglobin as a treatment for children and adults with SCD, a painful, sometimes life-threatening genetic disorder that deforms red blood cells and disrupts normal circulation. In the normal course of development, a biological switch flips during the production of hemoglobin, the oxygen-carrying component of red blood cells.

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 sickled shape. Drs. Rupon and Blobel reprogrammed gene expression to reverse the biological switch, causing cells to resume producing fetal hemoglobin, which is not affected by the SCD mutation, and produces normally shaped red blood cells.

The scientists built on previous work by Dr. Blobel’s team showing 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 used a specialized tool, a genetically engineered zinc finger protein, which they custom-designed to latch 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.

Drs. Rupon and Blobel will continue investigations aimed at moving their research toward clinical application. The approach may also prove useful in treating other diseases of hemoglobin, such as thalassemia, Dr. Rupon added.

For more information, see the press release about this study.

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