Cure for Sickle Cell Disease Close at Hand
Flipping a Gene Switch Reactivates Fetal Hemoglobin, May Reverse Sickle Cell Disease
Dec. 8, 2013 — Hematology researchers at The Children's
Hospital of Philadelphia 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.
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"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, M.D., Ph.D., of The Children's Hospital of Philadelphia. "If we can
translate this approach to humans, we may enable new treatment options for
patients."
Rupon presented the
team's findings today at a press conference during the annual meeting of the
American Society of Hematology (ASH) in New Orleans. Rupon worked in
collaboration with a former postdoctoral fellow, Wulan Deng, Ph.D., in the
laboratory of Gerd Blobel, M.D., Ph.D.
Hematologists have long
sought to reactivate fetal hemoglobin as a treatment for children and adults
with SCD, the 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. Regulatory elements in DNA shift
the body from producing the fetal form of hemoglobin to producing the adult
form instead. This transition occurs shortly after birth. When patients with
SCD undergo this transition, their inherited gene mutation distorts adult
hemoglobin, forcing red blood cells to assume a sickled shape.
In the current study,
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 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
(ZF) protein, which they custom-designed to latch onto a specific DNA site
carrying the code for fetal hemoglobin. They attached the ZF 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.
Rupon and Blobel will
continue investigations aimed at moving their research toward clinical
application. Rupon added that the approach may also prove useful in treating
other diseases of hemoglobin, such as thalassemia.
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