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“Delete-To-Recruit” – Scientists Discover Simpler Approach to Gene Therapy


Repositioning genes awakens fetal hemoglobin to treat disease. CRISPR editing may change future gene therapy. Researchers have discovered a promising new approach to gene therapy by reactivating genes that are normally inactive. They achieved this by moving the genes closer to regulatory elements on the DNA known as enhancers. To do so, they used CRISPR-Cas9 technology to cut out the piece of DNA separating the gene from its enhancer. This method could open up new ways to treat genetic diseases. The team demonstrated its potential in treating sickle cell disease and beta-thalassemia, two inherited blood disorders.

In these cases, a malfunctioning gene might be bypassed by reactivating an alternative gene that is usually turned off. This technique, called “delete-to-recruit,” works by altering the distance between genetic elements without introducing new genes or foreign material. The study was conducted by researchers from the Hubrecht Institute (De Laat group), Erasmus MC, and Sanquin, and published in the journal Blood.

Genes in our DNA contain the instructions for making proteins, which carry out many essential functions in cells. However, not all genes are active at all times. Some are only switched on when certain nutrients need to be processed, while others are active only during early development and later shut down. Proper cell function depends on tightly controlled gene activity. One important regulatory mechanism involves enhancers, which are segments of DNA that act like switches to turn genes on.
Bringing it closer

Enhancers can be located right next to the genes they regulate or positioned much farther away along the DNA. “In this study, we discovered that it’s possible to activate a gene by bringing it closer to an enhancer,” said Anna-Karina Felder, one of the study’s first authors. Felder and her colleagues Sjoerd Tjalsma, Han Verhagen, and Rezin Majied accomplished this using CRISPR-Cas9, a gene-editing tool that works like precise molecular scissors.

“We directed the scissors to cut out a piece of DNA between an enhancer and its gene, bringing them closer together,” Felder explained. “In adult cells, this successfully reactivated genes that are normally only active during embryonic development.” The researchers call this new method of gene activation “delete-to-recruit.”

Faulty hemoglobin


The new strategy offers hope for people with sickle cell disease and beta-thalassemia. In these inherited blood disorders, the adult globin gene does not function correctly. As a result, the body cannot produce normal hemoglobin, the protein that carries oxygen in red blood cells. Without properly formed hemoglobin, red blood cells break down too quickly, leading to serious and lifelong symptoms such as anemia, fatigue, and eventually organ damage. Many patients rely on regular blood transfusions to manage these conditions.

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.

Gene therapy, CRISPR technology, genetic engineering, genome editing, DNA sequencing, RNA interference, gene expression, transcription factors, epigenetics, genomics, personalized medicine, gene mutation, recombinant DNA, genetic testing, molecular genetics, hereditary diseases, gene regulation, synthetic biology, gene cloning, gene silencing

#GeneTherapy, #CRISPR, #GeneticEngineering, #GenomeEditing, #DNASequencing, #RNAi, #GeneExpression, #TranscriptionFactors, #Epigenetics, #Genomics, #PersonalizedMedicine, #GeneMutation, #RecombinantDNA, #GeneticTesting, #MolecularGenetics, #HereditaryDiseases, #GeneRegulation, #SyntheticBiology, #GeneCloning, #GeneSilencing

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