In order to increase hemoglobin levels, researchers at Children’s Hospital of Philadelphia (CHOP) have activated the creation of both fetal and adult hemoglobin. This treatment is a proof-of-concept for blood disorders such sickle cell disease and beta-thalassemia.
The researchers created a method to produce more hemoglobin using a single vector by using a viral vector designed to revive fetal hemoglobin production, decrease mutant hemoglobin, and supply functional adult hemoglobin. The results were published in Haematologica.
“Until now, researchers have been exploring one of two approaches to treating blood disorders like sickle cell disease or beta-thalassemia: adding a functional copy of the adult hemoglobin gene, or increasing production of fetal hemoglobin,” said senior author Stefano Rivella, PhD, Kwame Ohene-Frempong Chair on Sickle Cell Anemia and Professor of Pediatrics at CHOP. “In this study, we have done both simultaneously, which provides an opportunity to produce more hemoglobin per vector in these patients.”
Red blood cells contain the protein hemoglobin, which is responsible for carrying oxygen from the lungs to tissues all over the body. Sickle cell disease and beta-thalassemia are genetic blood illnesses brought on by mistakes in the hemoglobin gene.
Fetal hemoglobin is produced in utero by the gamma-globin gene, but after delivery, this gene is shut off and adult hemoglobin is produced by the beta-globin gene.
Individuals with beta-thalassemia and sickle cell disease have mutations in the beta-globin gene, which results in the synthesis of mutant hemoglobin and, as a result, in major health issues such as delayed growth, jaundice, pain crises, pulmonary hypertension, and stroke.
The goal of current research is to either increase fetal hemoglobin, which is not altered in these settings, or restore a functional copy of adult hemoglobin by gene therapy, which involves supplying new genetic material through an engineered vehicle called a viral vector.
Until now, researchers have been exploring one of two approaches to treating blood disorders like sickle cell disease or beta-thalassemia: adding a functional copy of the adult hemoglobin gene, or increasing production of fetal hemoglobin. In this study, we have done both simultaneously, which provides an opportunity to produce more hemoglobin per vector in these patients.
Stefano Rivella
However, there are limitations to both of these approaches, and neither has been established as a fully curative approach.
In order to increase hemoglobin levels in one therapy, the researchers led by co-first authors Danuta Jarocha, PhD and Silvia Lourenco, PhD combined the two tactics into a single gene therapy vector. They did this by concentrating on a transcription factor called BCL11A, which functions as a switch to turn on adult hemoglobin production and turn off fetal hemoglobin production.
The scientists reasoned that they could increase hemoglobin production if they used an engineered vector to repress BCL11A, which would maintain the generation of fetal hemoglobin and stop the development of mutant adult hemoglobin. They also added back a working copy of the beta-globin gene.
Working in cell lines of patients with sickle cell disease and beta-thalassemia, the researchers tested their vector which included a gene coding for adult hemoglobin and a microRNA sequence that would target BCL11A and found that the vector was able to elevate fetal and adult hemoglobin simultaneously in vitro.
Although BCL11A was not totally silenced, the inhibition was enough to lessen the amount of mutant adult hemoglobin produced. The vector was able to induce higher functional hemoglobin production than a vector expressing beta-globin alone because it increased both fetal and functional adult hemoglobin.
“Future studies will evaluate this approach using an even stronger vector that we developed in our lab and published on recently,” Rivella said. “Combining these two technologies, we hope to make an even more powerful vector that can provide curative levels of hemoglobin to these patients.”
The CuRED Frontier Program at CHOP, which is committed to discovering fresh and enhanced curative treatments for blood disorders like sickle cell disease and beta-thalassemia, provided funding for this study.
