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Researchers believe they have found a new way to treat anemias that are resistant to erythropoietin (EPO).
The team identified a pair of drugs, one that is already approved for use in the US, that can activate the cell receptor PPAR-α and synergize with low amounts of
glucocorticoids to increase red blood cell (RBC) production.
Their research is serving as the foundation for an upcoming clinical trial in patients with Diamond-Blackfan anemia (DBA).
Harvey Lodish, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described the research in a letter to Nature.
The team noted that certain anemias, such as DBA, cannot be treated with EPO. EPO controls RBC production by causing colony-forming-unit erythroids (CFU-Es) to divide and differentiate into RBCs. In DBA, the CFU-Es die before they can make RBCs, and patients have too few CFU-Es to make EPO treatment effective.
In 2010, Dr Lodish and his colleagues determined that glucocorticoids increase RBCs in EPO-resistant anemias by acting on burst-forming-unit erythroids (BFU-Es).
Glucocorticoids increase the likelihood that, when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which, in turn, produce more CFU-Es and, ultimately, more RBCs.
With this in mind, the researchers screened for drugs that could interact with and boost glucocorticoids’ activity.
Glucocorticoids act by binding to a receptor in the cytoplasm that migrates into the nucleus and affects the expression of multiple genes. So the team screened for drugs that inhibit or activate other nuclear receptors.
They found that two drugs used to treat lipid disorders worked with glucocorticoids to increase RBC production in vitro. Both of these drugs, GW7647 and fenofibrate, activate PPARα. Fenofibrate was approved by the US Food and Drug Administration in 2001 and has been used to treat high cholesterol in adults and children.
When the researchers studied the mechanism of action of glucocorticoids and GW7647/fenofibrate, they found the glucocorticoid receptor binds to approximately 1000 sites in the DNA and turns on a large number of genes.
Fenofibrate and GW7647 activate the PPARα receptor, which subsequently binds adjacent to the glucocorticoid receptor on the DNA. The receptors modulate genes that are critical for BFU-E cell self-renewal and ultimately produce more RBCs.
When combined with dexamethasone, treatment with either GW7647 or fenofibrate led to a 150-fold increase in erythroblast production, which is 3- to 5-fold greater than the increase observed with dexamethasone alone.
These results have led the researchers to begin a clinical trial to test the effectiveness of a glucocorticoid/fenofibrate treatment in children with DBA.
Beyond the treatment of DBA, the researchers are optimistic about the impact that glucocorticoid/fenofibrate treatment might have on seemingly unrelated conditions.
“Glucocorticoids represent one of the most prescribed classes of drugs,” said Xiaofei Gao, PhD, a researcher in the Lodish lab.
“Basically, if PPARα is important in a disease that is currently treated by glucocorticoids, we may have a new way to treat those diseases that reduces the harmful side effects of glucocorticoids. That could affect a lot of patients.” 
Researchers believe they have found a new way to treat anemias that are resistant to erythropoietin (EPO).
The team identified a pair of drugs, one that is already approved for use in the US, that can activate the cell receptor PPAR-α and synergize with low amounts of
glucocorticoids to increase red blood cell (RBC) production.
Their research is serving as the foundation for an upcoming clinical trial in patients with Diamond-Blackfan anemia (DBA).
Harvey Lodish, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described the research in a letter to Nature.
The team noted that certain anemias, such as DBA, cannot be treated with EPO. EPO controls RBC production by causing colony-forming-unit erythroids (CFU-Es) to divide and differentiate into RBCs. In DBA, the CFU-Es die before they can make RBCs, and patients have too few CFU-Es to make EPO treatment effective.
In 2010, Dr Lodish and his colleagues determined that glucocorticoids increase RBCs in EPO-resistant anemias by acting on burst-forming-unit erythroids (BFU-Es).
Glucocorticoids increase the likelihood that, when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which, in turn, produce more CFU-Es and, ultimately, more RBCs.
With this in mind, the researchers screened for drugs that could interact with and boost glucocorticoids’ activity.
Glucocorticoids act by binding to a receptor in the cytoplasm that migrates into the nucleus and affects the expression of multiple genes. So the team screened for drugs that inhibit or activate other nuclear receptors.
They found that two drugs used to treat lipid disorders worked with glucocorticoids to increase RBC production in vitro. Both of these drugs, GW7647 and fenofibrate, activate PPARα. Fenofibrate was approved by the US Food and Drug Administration in 2001 and has been used to treat high cholesterol in adults and children.
When the researchers studied the mechanism of action of glucocorticoids and GW7647/fenofibrate, they found the glucocorticoid receptor binds to approximately 1000 sites in the DNA and turns on a large number of genes.
Fenofibrate and GW7647 activate the PPARα receptor, which subsequently binds adjacent to the glucocorticoid receptor on the DNA. The receptors modulate genes that are critical for BFU-E cell self-renewal and ultimately produce more RBCs.
When combined with dexamethasone, treatment with either GW7647 or fenofibrate led to a 150-fold increase in erythroblast production, which is 3- to 5-fold greater than the increase observed with dexamethasone alone.
These results have led the researchers to begin a clinical trial to test the effectiveness of a glucocorticoid/fenofibrate treatment in children with DBA.
Beyond the treatment of DBA, the researchers are optimistic about the impact that glucocorticoid/fenofibrate treatment might have on seemingly unrelated conditions.
“Glucocorticoids represent one of the most prescribed classes of drugs,” said Xiaofei Gao, PhD, a researcher in the Lodish lab.
“Basically, if PPARα is important in a disease that is currently treated by glucocorticoids, we may have a new way to treat those diseases that reduces the harmful side effects of glucocorticoids. That could affect a lot of patients.”
Researchers believe they have found a new way to treat anemias that are resistant to erythropoietin (EPO).
The team identified a pair of drugs, one that is already approved for use in the US, that can activate the cell receptor PPAR-α and synergize with low amounts of
glucocorticoids to increase red blood cell (RBC) production.
Their research is serving as the foundation for an upcoming clinical trial in patients with Diamond-Blackfan anemia (DBA).
Harvey Lodish, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues described the research in a letter to Nature.
The team noted that certain anemias, such as DBA, cannot be treated with EPO. EPO controls RBC production by causing colony-forming-unit erythroids (CFU-Es) to divide and differentiate into RBCs. In DBA, the CFU-Es die before they can make RBCs, and patients have too few CFU-Es to make EPO treatment effective.
In 2010, Dr Lodish and his colleagues determined that glucocorticoids increase RBCs in EPO-resistant anemias by acting on burst-forming-unit erythroids (BFU-Es).
Glucocorticoids increase the likelihood that, when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which, in turn, produce more CFU-Es and, ultimately, more RBCs.
With this in mind, the researchers screened for drugs that could interact with and boost glucocorticoids’ activity.
Glucocorticoids act by binding to a receptor in the cytoplasm that migrates into the nucleus and affects the expression of multiple genes. So the team screened for drugs that inhibit or activate other nuclear receptors.
They found that two drugs used to treat lipid disorders worked with glucocorticoids to increase RBC production in vitro. Both of these drugs, GW7647 and fenofibrate, activate PPARα. Fenofibrate was approved by the US Food and Drug Administration in 2001 and has been used to treat high cholesterol in adults and children.
When the researchers studied the mechanism of action of glucocorticoids and GW7647/fenofibrate, they found the glucocorticoid receptor binds to approximately 1000 sites in the DNA and turns on a large number of genes.
Fenofibrate and GW7647 activate the PPARα receptor, which subsequently binds adjacent to the glucocorticoid receptor on the DNA. The receptors modulate genes that are critical for BFU-E cell self-renewal and ultimately produce more RBCs.
When combined with dexamethasone, treatment with either GW7647 or fenofibrate led to a 150-fold increase in erythroblast production, which is 3- to 5-fold greater than the increase observed with dexamethasone alone.
These results have led the researchers to begin a clinical trial to test the effectiveness of a glucocorticoid/fenofibrate treatment in children with DBA.
Beyond the treatment of DBA, the researchers are optimistic about the impact that glucocorticoid/fenofibrate treatment might have on seemingly unrelated conditions.
“Glucocorticoids represent one of the most prescribed classes of drugs,” said Xiaofei Gao, PhD, a researcher in the Lodish lab.
“Basically, if PPARα is important in a disease that is currently treated by glucocorticoids, we may have a new way to treat those diseases that reduces the harmful side effects of glucocorticoids. That could affect a lot of patients.”