New Hope For Sickle Cell Disease Treatment
A team of experts in childhood blood disorders, pathologists and developmental biologists, both from the University of Michigan (U-M) Health System in the US and the University of Tsukuba in Japan. found that increasing expression in the proteins TR2 and TR4, more than doubled the level of fetal hemoglobin produced in sickle cell mice and reduced organ damage.
They believe their "proof of concept study" is the first to target specific proteins to prevent a disease.
Sickle cell disease or sickle cell anemia, is an inherited blood disorder where a mutation in the haemoglobin gene causes a change in the shape and effectiveness of red blood cells. Instead of being round and soft, the cells become rigid and crescent (sickle) shaped, so they can't pass through small blood vessels.
The problem begins to develop in the first few weeks after birth, as fetal hemoglobin is replaced by adult hemoglobin.
The disease affects hundreds of thousands of people worldwide, who experience life-long debilitating pain episodes, chronic organ damage and significantly shorter lifespan.
A few patients, however, who are born with higher levels of fetal hemoglobin, show less severe complications and live longer, so boosting fetal hemoglobin is one way to treat the disease.
Lead author Dr Andrew D. Campbell, a pediatrician and director of the Pediatric Comprehensive Sickle Cell Program at the U-M Cancer Center, told the media:
"The vast majority of sickle cell disease patients are diagnosed early in childhood when adult hemoglobin normally replaces fetal hemoglobin, but the severity of the disease can differ markedly, correlating most strongly with the level of fetal hemoglobin present in red cells."
"Currently hydroxyurea is the only FDA approved drug known to increase the levels of fetal hemoglobin within sickle cell disease patients and a substantial number of patients do respond to it," he said, "But the long term consequences for hydroxyurea are unknown, especially in children."
In their study report, Campbell and colleagues describe how, using lab mice, they found a way to boost fetal hemoglobin levels by modulating TR2 and TR4 expression.
Senior author Dr James Douglas Engel, professor and chair of the U-M's Cell and Development Biology Department, said:
"While the average fetal hemoglobin was 7.6% in the sickle cell mice, the TR2/TR4 treated sickle cell mice had an average fetal hemoglobin of 18.6%."
He explains that the both anemia and red blood cell turnover improved in the TR2/TR4 treated sickle cell disease mice.
The authors write:
"In a "humanized" sickle cell model mouse, forced TR2/TR4 expression increased HbF abundance from 7.6% of total hemoglobin to 18.6%, accompanied by increased hematocrit from 23% to 34% and reticulocyte reduction from 61% to 18%, indicating a significant reduction in hemolysis."
They also describe how this lessened disease complications in the sickle cell disease (SCD) mice:
"Moreover, forced TR2/TR4 expression reduced hepatosplenomegaly and liver parenchymal necrosis and inflammation in SCD mice, indicating alleviation of usual pathophysiological characteristics. "
Engel says more studies should now be done, as should clinical trials, to determine whether the approach would work in humans.
Funds from the American Heart Association, Cooley's Anemia Foundation, Robert Wood Johnson Foundation and the National Institutes of Health's National Heart Lung and Blood, helped pay for the research.
Recommended related news
"Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated
disease phenotypes"; Andrew D. Campbell, Shuaiying Cui, Lihong Shi, Rebekah Urbonya, Andrea Mathias, Kori
Bradley, Kwaku O. Bonsu, Rhonda R. Douglas, Brittne Halford, Lindsay Schmidt, David Harro, Donald Giacherio, Keiji
Tanimoto, Osamu Tanabe, and James Douglas Engel; PNAS published ahead of print 31 October 2011;
DOI:10.1073/pnas.1104964108; Link to Abstract.
Additional source: University of Michigan Health System
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