San Raffaele Telethon Institute for Gene Therapy

Gene transfer technologies and new gene therapy strategies


Head of Unit

Luigi Naldini


Gene therapy can treat inherited diseases by replacing a malfunctioning gene with a functional copy of it in the affected cells, or by editing the mutant sequence to the common version. Moreover, cells can be instructed to better fight acquired diseases such as cancer and infections. To achieve these ambitious goals, this unit has long been developing platforms for safe and efficient gene transfer, mostly based on modified viruses, and for targeted gene editing, based on artificial endonucleases (such as ZFNs and CRISPR/Cas). Group researchers then exploit these tools for genetic engineering hematopoietic stem cells (HSC) or lymphocytes ex vivo, or liver cells in vivo, always focusing on the goal of a future clinical translation of the strategy to treat disease.

Group's early work laid the foundation for the current broad use of lentiviral vectors (LV), both in biomedical research and as advanced therapy medicinal products in several gene therapy clinical trials, carried out in our own Institute and several other centers worldwide. To date, a few hundred patients suffering from immuno- hematopoietic or neurodegenerative disease, or some type of cancer, have markedly benefited from ex vivo HSC or T-cell gene therapy. As our early research has now reached the clinic, the unit has back at the bench working on the next generation genetic engineering.


Research activity

HSC gene therapy will become safer and broadly applicable if we could use novel strategies to engraft engineered cells without relying on chemotherapy, and perform more precise engineering. Group researchers pioneered and continue to develop gene targeting using artificial nucleases to edit gene sequences. These strategies offer radical new solutions to overcome the major hurdles that have long hindered progress of the gene therapy field. Gene correction, as opposed to gene replacement, not only restores the function of a disease gene but also its physiological expression control, while avoiding the risk of vector insertional mutagenesis. The unit is optimizing application of gene editing in T-cells and HSC for treating some primary immune deficiencies.

Concomitantly, to increase the efficacy and safety of gene editing, this unit is devising strategies to select and expand the edited cells before or after in vivo administration. Researchers has also developed a platform for liver-directed in vivo gene therapy, which ensures specific, robust and stable transgene expression in hepatocytes, and can induce or re-establish antigen-specific immune tolerance. The group has shown the efficacy and safety of this platform for the gene therapy of hemophilia in both small and large animal models. They are currently engineering new stealth vectors, which escape innate and adaptive immune recognition following systemic administration, assess gene transfer into liver stem/progenitor cells, and aim to bring LV-mediated liver gene therapy to first-in-human testing in severe hemophilia patients. Group studies may pave the way for broader application of the platform to other diseases, such as metabolic diseases and lysosomal storage diseases, which can benefit from efficient correction of hepatocytes defects.