In Vivo Gene Therapy: A Step Toward More Accessible Treatments for Severe Genetic Blood Disorders

Led by Professor Luigi Naldini, Director of SR-Tiget and Full Professor of Histology at Vita-Salute San Raffaele University, and Dr. Alessio Cantore, Group Leader of the Liver Gene Therapy Unit at SR-Tiget, the team has identified a unique postnatal time frame that enables efficient and stable gene transfer into hematopoietic stem cells (HSCs). This breakthrough may expand access to life-saving gene therapies, making them safer and more broadly available.

Current gene therapy treatments often rely on ex vivo techniques, which involve harvesting the patient’s HSCs, modifying them in the lab, and reinfusing them after chemotherapy. While effective, these procedures are complex, invasive, and costly. In contrast, the SR-Tiget team’s in vivo strategy allows therapeutic vectors to be delivered directly into the body through a simple intravenous infusion—eliminating the need for cell manipulation or preconditioning.

Gene therapy aims to introduce a healthy copy of a defective gene into the patient’s cells using “vectors”—molecular carriers of genetic material. In this study, researchers used a lentiviral vector derived from a modified, replication-incompetent virus designed solely to deliver the therapeutic gene safely.

The team showed that administering lentiviral vectors during the first days of life resulted in long-term gene transfer into blood stem cells. This was possible due to a specific developmental window during which primitive stem cells circulate in the bloodstream while migrating from fetal hematopoietic organs to the bone marrow, where they settle and sustain lifelong blood cell production.

The key innovation was identifying and exploiting this early postnatal window to achieve gene transfer levels sufficient to correct or improve disease phenotypes in three distinct mouse models. Notably, this window could be extended using clinically approved mobilizing agents that increase the number of circulating HSCs.

The strategy was validated in models of three severe genetic diseases: Fanconi anemia (a bone marrow failure syndrome), adenosine deaminase–deficient severe combined immunodeficiency (ADA-SCID), and autosomal recessive osteopetrosis (ARO). In all cases, the approach showed significant therapeutic benefits.

“This study marks a significant turning point for the field,” says Michela Milani, first author and UniSR alumna. “It opens the door to treating genetic diseases at their earliest stages—often before irreversible damage occurs—right at the moment of diagnosis. By simplifying procedures from ex vivo to in vivo, we may be able to expand access to gene therapies in regions lacking specialized transplant centers and potentially reduce costs.”

In addition to demonstrating stable, multilineage gene transfer, the study revealed biological mechanisms that make early life uniquely favorable for this intervention. Intrinsic cellular factors and the dynamic nature of neonatal hematopoiesis enabled therapeutic efficacy without conditioning regimens or cell selection protocols.

The work provides a strong foundation for future preclinical studies and aligns with the growing implementation of newborn screening programs for genetic diseases. As the gene therapy landscape evolves, these findings represent a pivotal step toward clinical application of in vivo gene therapies for pediatric patients.

“We also identified circulating hematopoietic stem and progenitor cells in human newborns during the first few postnatal months, with levels declining with age—mirroring what we observed in mice,” concludes Professor Naldini. “These results support the future exploration of in vivo gene transfer strategies in pediatric patients.”