Scientists rewrite the rules of gene therapy by manipulating chromosome spacing

Researchers have developed a pioneering gene therapy strategy that physically repositions dormant genes on chromosomes to unlock their therapeutic potential. The “delete-to-recruit” technique uses precision DNA editing to eliminate spacer sequences, dramatically reactivating fetal globin genes that promises to provide new hope for
patients with sickle cell disease and beta-thalassemia.

A groundbreaking study published in Blood on 19 June 2025 has unveiled an entirely new paradigm for gene therapy that challenges conventional approaches to treating genetic disorders. The research demonstrates how the physical spacing of genes on DNA strands plays a crucial role in their activation, opening unprecedented therapeutic possibilities for hereditary blood diseases.

Revolutionary distance-based gene activation
The innovative “delete-to-recruit” (Del2Rec) methodology represents a fundamental shift from traditional gene therapy approaches. Rather than adding new genetic material or directly modifying faulty genes, this technique exploits the natural architecture of chromosomes to reactivate beneficial but dormant genes.

“In this study, we discovered that it’s possible to activate a gene by bringing it closer to an enhancer,” explains Anna-Karina Felder, one of the study’s first authors from the Hubrecht Institute. The research team, led by collaborators from the De Laat group, Erasmus MC, and Sanquin, used CRISPR-Cas9 technology as molecular scissors to precisely excise DNA segments between enhancers and their target genes.

The technique specifically targets the beta-globin gene cluster, where fetal globin genes (HBG) become naturally silenced after birth. In healthy development, adult globin genes take over haemoglobin production.

However, in conditions like sickle cell disease and beta-thalassemia, these adult genes are defective, leading to severe anaemia and life-threatening complications.

Mechanism of therapeutic gene reactivation
The research reveals that genomic distance serves as a critical regulatory mechanism for developmental gene silencing. The team demonstrated that “linear recruitment of the normally distal strong HBB enhancer to developmentally silenced embryonic HBE or fetal HBG promoters, through deletion or inversion of intervening DNA sequences, results in their strongly reactivated expression in adult erythroid cells.”

This discovery assigns new functional significance to previously considered “non-regulatory” DNA sequences. By maintaining physical separation between enhancers and genes, these genomic regions enable precise developmental control over gene expression programmes.

The Del2Rec strategy proved remarkably effective across multiple experimental models. In HUDEP-2 cells, a human adult erythroid cell line, the technique achieved 80-90% fetal haemoglobin production. Similar success was observed in patient-derived sickle cell disease cell lines and primary hematopoietic stem cells from healthy donors.

Therapeutic advantages over existing approaches
Current gene therapy for sickle cell disease and beta-thalassemia, approved in Europe in 2024, modifies globin repressor genes to reactivate fetal globin expression. However, this approach carries significant limitations, including extreme cost that restricts accessibility and potential unknown consequences from affecting multiple genes.

Del2Rec offers several compelling advantages. The technique specifically targets the physical relationship between enhancers and genes without introducing foreign genetic elements. “Editing the distance to an enhancer, instead of the genes themselves could offer a versatile therapeutic approach,” Felder concludes.

The research demonstrated that Del2Rec could circumvent both cost and safety concerns associated with current therapies. In sickle cell disease models, the technique markedly reduced cell sickling under hypoxic conditions, suggesting significant therapeutic potential.

Broader applications beyond globin disorders
The versatility of Del2Rec extends beyond beta-globin genes. The research team successfully applied the technique to the alpha-globin locus, reactivating the embryonic HBZ gene by recruiting the R2 enhancer. This broader applicability suggests the method could potentially address various genetic conditions where beneficial backup genes exist but remain developmentally silenced.

The study also revealed that both deletions and inversions of intervening DNA sequences could achieve gene reactivation, provided sufficiently strong enhancers were recruited to target gene promoters. This flexibility offers multiple strategic approaches for optimising therapeutic outcomes.

Technical precision and safety considerations
The Del2Rec methodology demonstrated remarkable precision in experimental applications. Digital droplet PCR analysis revealed that even when only 16% of chromosomal alleles carried the intended 25-kilobase deletion, substantial fetal globin reactivation occurred. Flow cytometry confirmed increased proportions of cells producing fetal haemoglobin, while high-performance liquid chromatography validated therapeutic protein levels.

Importantly, the technique preferentially activated the most proximal fetal globin gene (HBG2), suggesting efficient enhancer capture. Chromatin accessibility studies using ATAC-seq and histone modification analyses confirmed that Del2Rec induced genuine promoter reactivation rather than spurious transcriptional read-through.

Clinical translation potential
The research provides crucial groundwork for developing new therapeutic strategies. Testing in primary CD34+ hematopoietic stem and progenitor cells – the cells responsible for producing all blood cell types
– demonstrated that Del2Rec could function in clinically relevant cell populations.

“While we’re still in the early stages, this research lays important groundwork for the development of new gene therapies,” Felder notes. The approach showed comparable efficacy to existing BCL11A-targeting strategies while potentially offering greater specificity and reduced off-target effects.

The flexibility of Del2Rec in target site selection provides opportunities to optimise editing efficiency while minimising undesired genomic rearrangements – a significant advantage over single-target approaches that lack such adaptability.

What the future holds
This work fundamentally expands our understanding of genome organisation and gene regulation. The authors propose that “by providing linear separation they may support genes to autonomously control their transcriptional response to distal enhancers,” revealing new principles governing developmental gene expression.

Beyond immediate applications to hemoglobinopathies, Del2Rec could potentially address other genetic conditions where reactivating developmental backup genes might compensate for defective adult counterparts. The broader field of gene therapy could benefit from this alternative approach that manipulates enhancer-gene relationships rather than gene sequences themselves.

The research represents a paradigm shift toward understanding genome architecture as a therapeutic target, potentially revolutionising how we approach genetic disease treatment through spatial genomic manipulation rather than traditional gene addition or correction strategies.

Reference:
Felder, A. K., Tjalsma, S. J. D., Verhagen,
H. J. M. P., et. al. (2025). Reactivation of developmentally silenced globin genes through forced linear recruitment of remote enhancers. Blood, advance online publication.
https://doi.org/10.1182/blood.2024028128