Scientists from Johns Hopkins Medicine and eight other institutions in the United States, Africa and Europe say they have identified a potential new gene target that could be edited to treat sickle cell disease or SCD, an inherited blood disorder marked by sickle-shaped red blood cells that cause intense pain and shorten lifespans.
SCD is an inherited blood disorder that causes red blood cells to become hard, sticky, and sickle-shaped. These damaged blood cells generally clump together, impeding the flow of blood and reducing the ability for blood to carry oxygen to tissues and organs. This results in episodes of acute pain as well as long-term damage, causing a range of complications throughout life and increasing the risk of premature death.[1]
One common complication of SCD is abnormally high cerebral arterial velocities, an indicator of stenosis presence or reduced oxygen delivery to the brain, which can be associated with a greater risk of strokes and cognitive problems.[1]
SCD is the most common inherited genetic disease in France, but generally affects people from the Mediterranean, Southern Europe, Africa, Central America, South America, the Middle East, Asia, and India. In the United States, SCD affects more than 100,000 people, and worldwide 8 million people are affected. In the United States, 9 of 10 people who have sickle cell disease are of African ancestry or identify as Black with 1 in 13 Black babies carrying the sickle cell gene.[1][2]
Potential target
The potential target, the FLT1 gene*, contributes to the production of a protein, fetal hemoglobin, whose presence is already known to improve the lifespan of patients diagnosed with SCD. Scientists have been looking for ways to increase fetal hemoglobin in more people with sickle cell disease, says Ambroise Wonkam, M.D., Ph.D., the Henry J. Knott Director of the McKusick-Nathans Institute and Professor in Medical Genetics in the Department of Genetic Medicine at the Johns Hopkins University School of Medicine.
The scientists published results of their research, performed with funding support from the National Institutes of Health (NIH)**, March 1, 2025 in Nature Communications. [3] The research involved a genome-wide association study (GWAS), which analyzes gene sequencing data to find and connect variations in a specific gene with a certain trait or condition.
FLT1 is among 14 new genetic markers of fetal hemoglobin the scientists identified from GWAS data gathered and used with permission from 3,751 people with sickle cell disease. Fetal hemoglobin shuttles oxygen through veins and arteries in human fetuses, but is replaced by the adult version of hemoglobin shortly after birth. SCD affects only adult hemoglobin, causing it to clump and distort red blood cells into a sickle shape.
“Preserving fetal hemoglobin after birth at levels above 8% through gene editing is one critical, viable approach to saving more patients with sickle cell disease,” Wonkam explained.
Researchers estimate that 300,000 people are born with SCD each year, the majority of whom are in Sub-Saharan Africa. [4] In the United States, about 100,000 people have sickle cell disease, and the vast majority are non-Hispanic Black or African American, according to the Centers for Disease Control and Prevention (CDC). It is the most common form of an inherited blood disorder in the U.S., according to the American Society of Hematology (ASH).
Food and Drug Administration (FDA-) approved cell-based gene therapies help patients with a common, severe form of the condition produce more fetal hemoglobin in adult life and live longer. However, Wonkam believes that this approach can be improved by targeting other gene variants.
“Finding new genetic variants that could be edited to treat more patients, which would preserve the type of hemoglobin present at birth, is critical for saving more lives,” noted Wonkam.
“Other cures for sickle cell disease include stem cell or bone marrow transplants, which are not options for all patients,” Wonkam added.
Mapping more genes
In this study, Wonkam and the team of scientists used genetic tools to map more genes that regulate the level of fetal hemoglobin in Black populations in Cameroon, Tanzania and the United States.
To conduct their experiments, the scientists analyzed the whole genomes of 3,751 people with sickle cell disease, honing in on genes that regulate hemoglobin production. Using genotyping tools, they identified 14 novel locations of genes on various regions of the genome. Of the 14 genetic markers, FLT1, located on chromosome 13, had the strongest signal of gene expression, indicating its key role in producing fetal hemoglobin.
“Prior to this research, we only knew 10% to 20% of the gene locations that play a role in the production of fetal hemoglobin in African or African-descended individuals, compared with nearly 50% of the variation in genes that regulate fetal hemoglobin in European-descended individuals,” Wonkam explained.
“With the new genetic markers described in this study, we now know 90% of the genes associated with the production of fetal hemoglobin in sickle cell disease patients of African ancestry,” Wonkam concluded.
What’s next?
The researchers say they plan next to examine how FLT1 interacts with other genes at a molecular level in low-oxygen settings.
The scientists also hope to learn when in evolutionary time FLT1 became more common in African populations, which could help them identify similar genes to target.
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Note:* FLT1 is a member of VEGF receptor gene family. It encodes a receptor tyrosine kinase which is activated by VEGF-A, VEGF-B, and placental growth factor. The sequence structure of the FLT1 gene resembles that of the FMS (now CSF1R) gene, as a result, it is known as an acronym FLT for FMS-like tyrosine kinase.
** Funding support for the research was provided by the National Institutes of Health (1U01HG007459‐01, U24‐HL‐135600), the National Cancer Institute (P30 CA021765), the Childcare Foundation and the American Lebanese Syrian Associated Charities, a nonprofit organization that raises funds for St. Jude Children’s Research Hospital.
Reference
[1] Garcia D. Stem Cell Transplant for Sickle Cell Disease in Childhood Improves Health-Related Quality of Life a Decade Later. Onco’Zine. December 10, 2024 [Link]
[2] What Is Sickle Cell Disease? National Heart, Lung and Blood Institute. Online. Last accessed on December 4, 2024.
[3] 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. FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries. Nat Commun. 2025 Mar 1;16(1):2092. doi: 10.1038/s41467-025-57413-5. PMID: 40025045; PMCID: PMC11873275.
[4] Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, Temperley WH, Williams TN, Weatherall DJ, Hay SI. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013 Jan 12;381(9861):142-51. doi: 10.1016/S0140-6736(12)61229-X. Epub 2012 Oct 25. PMID: 23103089; PMCID: PMC3547249.
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