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blood cells from a mouse
Image courtesy of
University of Michigan
Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).
The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.
Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.
The team reported these findings in The Journal of Clinical Investigation.
Previous research showed that suppressing BCL11A can replace the defective beta
hemoglobin that causes sickling with healthy fetal hemoglobin.
“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.
“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”
However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).
To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.
Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.
To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.
HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.
When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers
of reticulocytes.
Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia. 
blood cells from a mouse
Image courtesy of
University of Michigan
Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).
The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.
Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.
The team reported these findings in The Journal of Clinical Investigation.
Previous research showed that suppressing BCL11A can replace the defective beta
hemoglobin that causes sickling with healthy fetal hemoglobin.
“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.
“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”
However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).
To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.
Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.
To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.
HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.
When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers
of reticulocytes.
Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.
blood cells from a mouse
Image courtesy of
University of Michigan
Preclinical research suggests a novel gene therapy may be effective against sickle cell disease (SCD).
The therapy is designed to selectively inhibit the fetal hemoglobin repressor BCL11A in erythroid cells.
Researchers found this was sufficient to increase fetal hemoglobin production and reverse the effects of SCD in vivo, without presenting the same problems as ubiquitous BCL11A knockdown.
The team reported these findings in The Journal of Clinical Investigation.
Previous research showed that suppressing BCL11A can replace the defective beta
hemoglobin that causes sickling with healthy fetal hemoglobin.
“BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle cell mutation,” explained study author David A. Williams, MD, of Boston Children’s Hospital in Massachusetts.
“So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”
However, Dr Williams and his colleagues found that ubiquitous knockdown of BCL11A impaired the engraftment of human and murine hematopoietic stem cells (HSCs).
To circumvent this problem, the researchers set out to silence BCL11A only in erythroid cells.
Selectively knocking down BCL11A involved several layers of engineering. As the core of their gene therapy vector, the researchers used a short hairpin RNA that inactivates BCL11A. To get it into cells, they embedded the short hairpin RNA in a microRNA that cells generally recognize and process.
To make this assembly work in the right place at the right time, the team hooked it to a promoter of beta hemoglobin expression, together with regulatory elements active only in erythroid cells. Finally, they inserted the whole package into a lentivirus.
HSCs from mice and SCD patients were then exposed to the manipulated virus, taking up the new genetic material. The resulting genetically engineered erythroid cells began producing fetal hemoglobin rather than the mutated beta hemoglobin.
When HSCs treated with this gene therapy were transplanted into mice with SCD, the cells engrafted successfully and reduced signs of SCD—namely, hemolytic anemia and increased numbers
of reticulocytes.
Dr Williams believes this approach could substantially increase the ratio of non-sickling to sickling hemoglobin in SCD. He also said the approach could be beneficial in beta-thalassemia.