Researchers are developing a proof-of-concept treatment that elevates adult and fetal hemoglobin


Stefano Rivella, PhD, Kwame Ohene-Frempong Chair in Sickle Cell Anemia and Professor of Pediatrics at CHOP. Credit: CHOP

Researchers at Philadelphia Children’s Hospital (CHOP) have developed a proof-of-concept treatment for blood disorders such as sickle cell disease and beta-thalassemia that could increase hemoglobin levels by activating both production. of fetal hemoglobin as an adult. Using a viral vector designed to reactivate fetal hemoglobin production, suppress mutant hemoglobin, and supply functional adult hemoglobin, the researchers developed an approach that could produce more hemoglobin through a single vector. The results were published in Hematological.

“So far, researchers have been exploring one of two approaches to dealing with it I like or beta-thalassemia: add a functional copy of the gene or increased fetal production “said lead author Stefano Rivella, Ph.D., Kwame Ohene-Frempong chair on sickle cell anemia and professor of pediatrics at CHOP.” In this study, we did both at the same time, which provides the opportunity to produce more hemoglobin per vector in these patients. “

Sickle cell disease and beta-thalassemia are genetic disorders of the blood caused by errors in the for hemoglobin, a protein that is found in red blood cells and carries oxygen from the lungs to tissues throughout the body. In the womb, the gamma-globin gene produces fetal hemoglobin, but after birth, this gene is turned off and the beta-globin gene, which produces adult hemoglobin, is activated. Patients with sickle cell disease and beta-thalassemia have mutations in the beta-globin gene, which lead to the production of mutant hemoglobin and, consequently, serious health complications, ranging from delayed growth and jaundice until crises of pain, pulmonary hypertension and stroke.

Current research has focused on the treatment of these blood disorders, either by increasing fetal hemoglobin, which is not mutated under these conditions, or by adding a functional copy of adult hemoglobin through gene therapy, using a engineering vehicle known as to supply new genetic material. However, there are limitations in these two approaches and neither has been established as a completely curative approach.

In order to increase in a single therapy, the researchers, led by co-authors Danuta Jarocha, Ph.D. and Silvia Lourenco, PhD – combined the two tactics into one vector. To do so, they focused on a transcription factor called BCL11A, which effectively works the switch that turns off fetal hemoglobin production and activates adult hemoglobin production. The researchers hypothesized that if they could use a vector designed to suppress BCL11A, which would keep fetal hemoglobin production active and deactivate mutant adult hemoglobin production, while adding a functional copy of the beta-globin gene, they could induce increased hemoglobin production.

Working on cell lines of patients with sickle cell disease and beta-thalassemia, the researchers tested their vector, which included a gene encoding adult hemoglobin and a microRNA sequence that would target BCL11A. and found that the vector was capable of elevating the fetus and adult. hemoglobin simultaneously in vitro. Although BCL11A was not completely overthrown, suppression was sufficient to reduce the production of the mutant adult hemoglobin. By elevating both fetal and functional adult hemoglobin, the vector was able to induce more functional hemoglobin production than that of a vector expressing beta-globin alone.

“Future studies will evaluate this approach using an even stronger vector that we have developed in our lab and recently published,” Rivella said. “Combining these two technologies, we hope to create an even more potent vector that can provide healing hemoglobin levels to these patients.”

This research was supported by the CHOP’s CuRED Frontier program, which is dedicated to finding new and improved curative therapies for blood disorders such as sickle cell disease and beta-thalassemia.

Gene Therapy Adjustment: Scientists Experimentally Increase Red Blood Cells to Help Sickle and Other Hemoglobin Diseases

More information:
Silvia Pires Lourenco et al, The inclusion of a shRNA targeting BCL11A in a vector expressing β-globin allows the simultaneous synthesis of curative adult and fetal hemoglobin, Hematological (2021). DOI: 10.3324 / haematol.2020.276634

CitationResearchers develop concept test treatment that elevates adult and fetal hemoglobin (2021, June 1) recovered on June 1, 2021 at -concept-treatment-elevates- adult-fetal.html

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