Researchers have unveiled a promising gene therapy technique that activates dormant genes by changing their proximity to regulatory elements known as enhancers. Using CRISPR-Cas9 to cut out segments of DNA, the team successfully reactivated helpful but typically silent genes without inserting new genetic material. This breakthrough, detailed in Blood Journal, may open doors for treating serious genetic blood disorders.
CRISPR-Cas9 Enables ‘Delete-to-Recruit’ Strategy
As reported by medicalxpress, the research team—from the Hubrecht Institute (De Laat group), Erasmus MC, and Sanquin—developed a technique called “delete-to-recruit.” They used CRISPR-Cas9, a precision gene-editing tool, to remove stretches of DNA between a gene and a distant enhancer. By shortening this distance, they brought the enhancer close enough to reactivate the gene.
“Normally, these genes are only active during embryonic development,” explains co-first author Anna-Karina Felder. “But in adult cells, we managed to switch them back on simply by adjusting their position relative to the enhancer.”
Potential Cure for Sickle Cell Disease and Beta-Thalassemia
This strategy shows particular promise for sickle cell disease and beta-thalassemia—both caused by mutations in the adult globin gene. These conditions impair hemoglobin production, resulting in anemia, fatigue, and organ damage. Currently, patients often rely on frequent blood transfusions and expensive gene therapies.
However, the fetal globin gene, which is active before birth and silenced afterward, could serve as a “backup engine.” The delete-to-recruit method reactivates this gene, restoring functional hemoglobin in red blood cells.
Proof of Concept in Human Cells
The team demonstrated this approach in cells from healthy donors and sickle cell patients. Most importantly, they confirmed the method’s success in human blood stem cells—the cells responsible for generating all blood components. Reactivating fetal globin in these cells could lead to long-term correction of defective red blood cells.
Beyond Blood Disorders: A Versatile Platform
While this research focuses on blood diseases, the implications are broader. The method could be applied to other genetic conditions where activating a backup gene might compensate for a faulty one. Unlike traditional gene therapies, this technique does not alter the gene itself but adjusts enhancer proximity—potentially avoiding off-target effects and reducing cost barriers.
A Promising Alternative to Existing Therapies
Current gene therapies for sickle cell disease, though effective, remain costly and can unpredictably affect other genes. In contrast, delete-to-recruit offers a targeted and potentially safer solution. Felder emphasizes, “We’re still in early stages, but this approach may lead to more accessible and precise gene therapies in the near future.”