Paper of the field n°8

Click here to read more about the next-generation in vivo gene editing of human hematopoietic stem and progenitor cells!

Abstract for General public

Ex vivo gene editing has become an established treatment for sickle cell disease (SCD) over the past decade. However, this strategy is limited by the high cost and complexity of manufacturing modified cells, as well as safety concerns related to the conditioning treatments required before reinfusing the edited cells. To overcome these challenges, scientists are developing new approaches that directly correct hematopoietic stem cells (HSCs) inside the body, allowing them to naturally produce healthy red blood cells.

This study investigates a promising method that uses virus-like particles (VLPs)—tiny, non-infectious shells that mimic viruses—to deliver gene-editing tools directly to human HSCs in vivo. The researchers engineered VLPs with specialized “envelopes” that help them enter HSCs more efficiently. Their goal was to apply genome-editing strategies that reactivate fetal hemoglobin (HbF), a therapeutic approach already shown to effectively reduce or reverse the sickling of red blood cells.

In laboratory experiments and in mouse models, these engineered VLPs were injected into humanized mice and successfully delivered CRISPR-based gene-editing components into human HSCs. One approach used an adenine base editor (ABE) to reduce the expression of a transcription factor that normally suppresses HbF production. This resulted in up to 26% editing efficiency and 22% HbF induction. A second strategy directly targeted the γ-globin genes using the CRISPR–Cas9 system, achieving 7.5% editing efficiency and 15% HbF induction. Importantly, both approaches preserved the normal growth and function of the edited HSCs.

Although additional optimization will be needed to reach clinically relevant levels of gene correction, this work provides strong evidence that in vivo editing of HSCs may be feasible, potentially eliminating the need for complex transplantation procedures.

Overall, the study suggests that envelope-engineered VLPs could become a powerful, safer, and more accessible therapeutic platform for treating genetic blood disorders such as SCD.

Abstract written by Letizia Fontana from Imagine Institute (France)

Botchkarev, Vladimir V., et al. « In Vivo Gene Editing of Human Hematopoietic Stem and Progenitor Cells Using Envelope-Engineered Virus-like Particles ». Nature Biotechnology, décembre 2025, p. 1‑13. www.nature.com, https://doi.org/10.1038/s41587-025-02915-2