Bringing it closer
Enhancers can be located next to the gene they control, but can also be far away on the DNA. “In this study, we discovered that it’s possible to activate a gene by bringing it closer to an enhancer,” says Anna-Karina Felder, one of the study’s first authors. Felder and her colleagues Sjoerd Tjalsma, Han Verhagen and Rezin Majied achieved this by using CRISPR-Cas9, a technology acting as molecular scissors that can be guided very precisely to cut the DNA. “We directed the scissors to cut out a piece of DNA between an enhancer and its gene, bringing them closer together,” Felder explains. “In adult cells, this successfully reactivated genes that are normally only active during embryonic development”. The team refers to this entirely new way of reactivating genes as ‘delete-to-recruit’.
Faulty hemoglobin
The new strategy offers hope for patients with sickle cell disease and beta-thalassemia. In these genetic blood diseases, the adult globin gene is broken. This causes the protein hemoglobin, responsible for carrying oxygen in our red blood cells, to not form properly. As a result, red blood cells are broken down too quickly and patients suffer serious lifelong symptoms such as anemia, fatigue and, eventually, organ damage. Blood transfusions are often necessary.
Restarting the backup engine
Delete-to-recruit technology could be used to treat these patients by harnessing the fetal globin gene. This gene is naturally active before birth, and part of the hemoglobin produced within the fetus. Once the child is born, it is switched off. “In people with sickle cell disease or beta-thalassemia, it’s the adult globin gene—the main engine that powers red blood cells—that is broken. But fetal globin is like a backup engine. By switching it back on, we can repower the red blood cells and possibly cure these patients,” Felder says.
The team collaborated with researchers at Erasmus MC (Philipsen) and Sanquin (Van den Akker) to show that this strategy works in cells from human healthy donors and patients with sickle cell disease. Particularly important is that the team confirmed its efficacy in blood stem cells. These cells are responsible for producing the variety of blood cells in our body, including red blood cells. By reactivating fetal globin in blood stem cells, these cells can give rise to healthy red blood cells instead of broken ones.
New possibilities
“While we’re still in the early stages, this research lays important groundwork for the development of new gene therapies,” Felder says. This goes beyond the scope of genetic blood diseases, as the new method could also be applied to other diseases where insufficient amounts of healthy proteins can be compensated by restarting a ‘backup engine gene’. The broader field of gene therapy could thus benefit from delete-to-recruit technology, because it uses a different approach than currently available therapies. “Editing the distance to an enhancer, instead of the genes themselves could offer a versatile therapeutic approach,” Felder concludes.
For patients with sickle cell disease and thalassemia, the new approach could—in the future—provide an alternative to the currently available gene therapy. While the existing gene therapy was approved for use in Europe in 2024, it is very expensive, which limits its accessibility. Moreover, this treatment modifies a globin repressor gene, which indeed causes reactivation of fetal globin, but may well have effects on other genes as well, with unknown consequences for the patient. Delete-to-recruit may circumvent both problems.
Reference: Felder AK, Tjalsma SJD, Verhagen HJMP, et al. Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers. Blood. 2025. doi: 10.1182/blood.2024028128
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