Researchers from Dana-Farber/Boston Children's Cancer and Blood
Disorders Center have found that changes to a small stretch of DNA may
circumvent the genetic defect behind sickle cell disease (SCD). The
discovery, published in the journal Nature, creates a path for
developing gene editing approaches for treating SCD and other hemoglobin
disorders, such as thalassemia.
This stretch of DNA, called an enhancer, controls the molecular switch
BCL11A. This switch, in turn, determines whether a red blood cell
produces the adult form of hemoglobin--which in SCD is mutated--or a
fetal form that is unaffected by and counteracts the effects of the
sickle mutation. Other studies indicate that sickle cell patients with
elevated levels of fetal hemoglobin have a milder form of the disease.
The new Nature study--led by Stuart Orkin, MD, and Daniel Bauer, MD,
PhD, of Dana-Farber/Boston Children's, and Feng Zhang, PhD, of the Broad
Institute of MIT and Harvard--was spurred by the discovery that
naturally occurring beneficial variations in the DNA sequence in this
enhancer dial down BCL11A only in red blood cells.
To mimic and improve upon the effects of these variations, the research
team used recently developed CRISPR-based gene editing tools to
systematically cut out tiny sections of DNA step-by-step along the
entire length of the enhancer in blood stem cells
from human donors. They then allowed the cells to mature into red blood
cells and found that the amount of fetal hemoglobin the cells produced
had increased substantially. The team's experiments revealed a specific
location in the enhancer that when cut leads to production of high
levels of fetal hemoglobin. Parallel experiments in an animal model
revealed that removal of this part of the enhancer affected BCL11A's
expression only in red blood cells, not in immune or brain cells, where
BCL11A is also active. These findings show that the effects are
restricted to red blood cells, and that other cell types are unaffected.
"There was no efficient way of conducting this kind of experiment until
now," said Bauer, a pediatric hematologist/oncologist at
Dana-Farber/Boston Children's. "Our goal was to break the enhancer,
rather than fix the hemoglobin mutation, but to do so in very precise
ways that are only possible since gene editing technologies like CRISPR
became available."
Interest in exploring the potential clinical uses of the BCL11A switch
has grown since Orkin's laboratory revealed its direct role in the
transition from fetal to adult hemoglobin in Nature in 2009. Another
important step came in 2013, when the journal Science published their
report of the discovery of the enhancer that directs expression of
BCL11A only in red blood cells.
"We've now targeted the modifier of the modifier of a disease-causing
gene," explained Orkin, a leader of Dana-Farber/Boston Children's who
serves as chairman of pediatric oncology at Dana-Farber Cancer Institute
and associate chief of hematology/oncology at Boston Children's
Hospital. "It's a very different approach to treating disease."
The data provide proof of principle that targeted edits to BCL11A's
enhancer in blood stem cells could be an attractive approach for curing
SCD and related conditions.
"These experiments may have revealed the genetic Achilles heel of sickle
cell disease," said Orkin. "Alterations to these specific portions of
the enhancer have the same effect as knocking the whole enhancer out
altogether, suggesting that this could be a promising strategy to
translate into the clinic."
"Although fixing the sickle mutation itself would seem the most
straightforward approach, it turns out that blood stem cells, the
ultimate targets for this kind of therapy, are much more resistant to
genetic repair than to genetic disruption," Bauer added. "Therefore,
making a single DNA cut that breaks the enhancer solely in blood stem
cells could be a much more feasible strategy."
More at http://www.medicalnewstoday.com/categories/blood
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