07 June 2021

US scientists have developed a proof-of-concept treatment for blood disorders such as sickle cell disease and beta-thalassaemia.

Researchers at Children’s Hospital of Philadelphia (CHOP) have developed a viral vector which can raise functional haemoglobin levels by activating production of both foetal and adult haemoglobin, while at the same time suppressing mutant haemoglobin.

Up until now, research into new genetic treatments for sickle cell disease and beta-thalassaemia have focused on either increasing foetal haemoglobin, which is not mutated in these conditions, or adding back a functional copy of adult haemoglobin via gene therapy, using a viral vector to supply new genetic material.

However, there are limitations to both approaches, and neither has been established as a fully curative approach, according to the researchers.

In this study, which is published in Haematologica, the research team combined the two approaches into a single gene therapy vector.

The BCL11A transcription factor operates the switch that turns off the production of foetal haemoglobin and turns on the production of adult haemoglobin. The team developed an engineered viral vector with a microRNA sequence that could repress BCL11A. The viral vector also included a functional copy of the beta-globin gene to induce adult haemoglobin production.

The researchers worked in blood cell lines, genetically engineered to replicate sickle cell disease and beta-thalassaemia, to test the viral vector. They found it could elevate foetal and adult haemoglobin simultaneously. Although BCL11A was not completely knocked down, the suppression was sufficient to reduce production of the mutant adult haemoglobin.

By elevating both foetal and functional adult haemoglobin, the vector was able to induce more functional haemoglobin production than that of a vector expressing beta-globin alone.

Senior author Dr Stefano Rivella, Kwame Ohene-Frempong chair on Sickle Cell Anaemia and professor of paediatrics at CHOP, said: “Future studies will evaluate this approach using an even stronger vector that we developed in our lab and published on recently.

“Combining these two technologies, we hope to make an even more powerful vector that can provide curative levels of haemoglobin to these patients.”


Pires Lourenco S, Jarocha D, Ghiaccio V, Guerra A, Abdulmalik O, La P, Zezulin A, Smith-Whitley K, Kwiatkowski JL, Guzikowski V, Nakamura Y, Raabe T, Breda L, Rivella S. (2021) “Inclusion of a shRNA targeting BCL11A into a beta-globin expressing vector allows concurrent synthesis of curative adult and fetal haemoglobin.” Haematologica, doi: 10.3324/haematol.2020.276634


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