Researchers have identified novel genetic variants which may lead to a new gene therapy for sickle cell disease.
Sickle cell disease is a genetic disease affecting adult haemoglobin. One option to treat the disease is to increase levels of foetal haemoglobin (HbF), which is unaffected by sickle cell disease mutations but normally disappears shortly after birth. The aim would be to keep HbF levels at about 8%.
Scientists are searching for variations in the genome which influence the production of HbF, that could be edited to create a gene therapy to improve survival of people with sickle cell.
However, while 50% of the genetic variation in HbF levels in European individuals has been explained, for African or African-descended individuals, only 10-20% of the variation has been found to date.
To identify these missing variations, researchers from the USA, Africa and Europe analysed the genomes from 3,751 people with sickle cell disease, from Cameroon and Tanzania, and African Americans.
The team identified variants in 14 new locations in the genome which were associated with levels of HbF. One of the new locations, the FLT1 gene had the strongest association, and could become a new target for gene editing therapy for sickle cell disease.
With the identification of these 14 new genetic markers, the researchers say that 90% of the genetic variants associated with HbF in people with African ancestry have now been identified. The results have been published in Nature Communications.
The team now plan further research into the activity of FLT1 to see how it interacts with other genes under low oxygen conditions.
Study leader Professor Ambroise Wonkam, professor of medical genetics at the Johns Hopkins University School of Medicine, said: “Prior to this research, we only knew 10% to 20% of the gene locations that play a role in the production of fetal haemoglobin in African or African-descended individuals, compared with nearly 50% of the variation in genes that regulate fetal haemoglobin in European-descended individuals.
“With the new genetic markers described in this study, we now know 90% of the genes associated with the production of fetal haemoglobin in sickle cell disease patients of African ancestry.
“Finding new genetic variants that could be edited to treat more patients, which would preserve the type of haemoglobin present at birth, is critical for saving more lives.”
Source:
Wonkam A, Esoh K, Levine RM, Ngo Bitoungui VJ, Mnika K, Nimmagadda N, Dempsey EAD, Nkya S, Sangeda RZ, Nembaware V, Morrice J, Osman F, Beer MA, Makani J, Mulder N, Lettre G, Steinberg MH, Latanich R, Casella JF, Drehmer D, Arking DE, Chimusa ER, Yen JS, Newby GA, Antonarakis SE. (2025) “FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries.” Nature Communications, 1 March 2025, doi: 10.1038/s41467-025-57413-5.
Link: https://www.nature.com/articles/s41467-025-57413-5
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