Large-scale discovery of potent, compact and erythroid specific enhancers for gene therapy vectors

Nikoletta Psatha (), Pavel Sova, Grigorios Georgolopoulos, Kiriaki Paschoudi, Mineo Iwata, Jordan Bloom, Tatyana Ulyanova, Hao Wang, Alexandra Kirtsou, Ninos-Ioannis Vasiloudis, Matthew S. Wilken, John A. Stamatoyannopoulos, Evangelia Yannaki, Thalia Papayanopoulou, George Stamatoyannopoulos and Jeff Vierstra ()
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Nikoletta Psatha: Altius Institute for Biomedical Sciences
Pavel Sova: Altius Institute for Biomedical Sciences
Grigorios Georgolopoulos: Altius Institute for Biomedical Sciences
Kiriaki Paschoudi: Aristotle University of Thessaloniki
Mineo Iwata: Altius Institute for Biomedical Sciences
Jordan Bloom: Altius Institute for Biomedical Sciences
Tatyana Ulyanova: University of Washington
Hao Wang: Altius Institute for Biomedical Sciences
Alexandra Kirtsou: Aristotle University of Thessaloniki
Ninos-Ioannis Vasiloudis: Aristotle University of Thessaloniki
Matthew S. Wilken: Altius Institute for Biomedical Sciences
John A. Stamatoyannopoulos: Altius Institute for Biomedical Sciences
Evangelia Yannaki: University of Washington
Thalia Papayanopoulou: University of Washington
George Stamatoyannopoulos: University of Washington
Jeff Vierstra: Altius Institute for Biomedical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Gene expression during cell development and differentiation is orchestrated by distal regulatory elements that precisely modulate cell selective gene activity. Gene therapy vectors leverage these elements for precise spatiotemporal transgene expression. Here, we develop a one-shot approach to screen candidate regulatory sequences from large-scale epigenomics data for programmable transgene expression within gene therapy viral vectors. We assess a library of 15,000 short sequences derived from developmentally active elements during erythropoiesis using a clinically relevant reporter vector. These elements display a gradient of transcriptional enhancer activity in erythroid cells, with high cell type restriction and developmental stage specificity. Finally, replacing the canonical β-globin μLCR with a compact enhancer in a β-thalassemia lentiviral vector successfully corrects the thalassemic phenotype in patient-derived hematopoietic and stem and progenitor cells (HSPCs), while increasing viral titers and cell transducibility. Our approach provides further insights into enhancer biology with wider implications for human gene therapy.

Date: 2025
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DOI: 10.1038/s41467-025-59235-x

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