The San Raffaele Telethon Institute For Gene Therapy – SR-TIGET (MI)

The Institute, led by Luigi Naldini, is world-recognized centre of excellence for research and clinical translation of advanced therapies. Founded in 1996 as a joint venture between Fondazione Telethon and Ospedale San Raffaele in Milan,  has the mission of performing cutting-edge research in gene and cell therapy and to translate its results into therapeutic advances, focusing mainly on rare genetic diseases. 

More recently SR-Tiget has also embarked on developing applications of its cell and gene therapy platforms to the treatment of certain types of cancer. 

In its almost 30-year history, SR-Tiget has provided pioneering and continued contributions to the gene and cell therapy field with relevant discoveries in vector design, gene transfer and gene editing strategies, stem cell biology, identity and mechanism of action of regulatory cells in immune responses and innate immune cells in cancer. 

SR-Tiget was among the first gene therapy Institutes worldwide able to embrace the full journey of Advanced Therapy Medicinal Product (ATMP) development - from the discovery of therapeutics to preclinical modelling, regulatory strategy, treatment of patients in first-in human phase I/II clinical trials and finally market registration - setting a new model for translational research in gene therapy.

This visionary model led to two out of the nine gene therapy drugs currently on EU market for genetic diseases: 

The institute is a world leader in gene therapy based on the use of vectors obtained from the virus responsible for AIDS, HIV, and was among the first to contribute to another frontier field, that of gene editing.

Other three gene therapy drugs are in advanced phases of development for the treatment of Wiskott-Aldrich syndrome, Mucopolysaccaridosis type I and Beta-Thalassemia.  

SR-Tiget pioneered the development of the lentiviral vector platform (viral vectors originally derived from the virus responsible for AIDS, HIV), which is now one of the most widely employed tools in biomedical research: what was initially perceived as an elegant proof of principle of an unlikely and fearsome technology has evolved into a cornerstone of modern biomedical science, whose applications include ex vivo and in vivo gene therapy, cancer immunotherapy, vaccine manufacturing, gene discovery and target validation in cellular and animal models, generation of transgenic animals. 

SR-Tiget also made important contributions to the field of genome editing, steadily contributing to its advances for the treatment of human diseases and providing experimental frameworks and tools that are now widely adopted by the gene editing community.  

The institute employs about 300 people in research and development, clinical research, administration and research management. 

Under the guidance of Luigi Naldini, 18 research groups focus both on fundamental and translation research projects, which span from the development of gene therapy and (epi)genome editing approaches, to the study of the biological properties of cells and their behavior to manipulation, the investigation of disease mechanisms and biological processes. The Institute’s unique ecosystem enables a continuum between research laboratories and clinical units that nurtures a virtuous bench-to-bedside and back cycle where clinical results inform laboratory research, that in turn enables clinical protocols improvements – making translational medicine a tangible reality. 

The treatments developed at SR-Tiget are transforming the lives of children from all continents. So far, over 150 patients - affected by five different diseases - have successfully received treatment. SR-Tiget is the top-ranking centre in the world for hematopoietic stem cell-based gene therapy for genetic disease both for the total number of patients treated, disease types and overall successful outcome: about one fourth of all patients treated with hematopoietic stem cell-based gene therapy worldwide have been treated at our Institute.  

This translation from laboratory research to patient therapies is made possible by several unique features of the Institute:

SR-Tiget research is organized along five strategic lines, each dedicated to a particular therapeutic strategy and goal. These lines integrate fundamental biology with cutting-edge technologies to drive the development of transformative therapies. 

Ex vivo gene therapy involves the genetic correction of patient hematopoietic stem cells (HSC) through viral vectors that have been modified to provide functional versions of defective genes. Once corrected, the cells are reinfused into the patients, where they engraft and are able to restore the missing function to the body. This research area has the long-term goal of advancing HSC gene therapy to standard-of-care for some rare genetic diseases. 

This approach has already been successfully applied by SR-Tiget for diseases of the immune system (ADA-SCID, Wiskott-Aldrich syndrome), blood (beta thalassemia), nervous system (metachromatic leukodystrophy) and metabolism (Hurler syndrome). Research is currently ongoing in the Institute to apply the same strategy to other genetic diseases, including osteopetrosis and lysosomal storage diseases such as alpha-mannosidosis, mucopolysaccharidosis type 4 A and B. 

Within this research area, SR-Tiget scientists also investigate biological properties of HSCs and hematopoiesis relevant for translation, a optimize HSC manipulation protocols, and rigorously assess safety aspects, including vector integration profiles and genotoxicity assessments, to ensure both efficacy and patient safety. 

The research groups involved are those of:

It allows to provide working versions of defective genes by administering the vector directly into the patient's body.

The goal of the institute's researchers is to be able to apply this therapeutic approach to hemophilia, by administering the lentiviral vector in the blood, or to genetic diseases of the nervous system such as leukodystrophies or gangliosidosis through an intracerebral injection.

The research groups involved are those of:

Provides for the timely correction of defects responsible for genetic diseases through real molecular scalpels that are delivered into the cells to modify genes that do not work (genetic editing) or to turn off toxic genes (epigenetic editing). Similar to gene therapy, the correction can occur either outside (ex vivo) or inside (in vivo) the body.

The objective of the institute, which has already made an important contribution of knowledge to this emerging field, is to study the potential of ex vivo gene editing for primary immunodeficiencies in which "traditional" gene therapy is not applicable (Omenn syndrome and hyperIgM), and in vivo epigenetic editing to turn off the genes responsible for genetic diseases characterized by the production of a toxic protein (Huntington's disease, familial hypercholesterolemia).

The research groups involved are those of:

In addition to being our natural defense against pathogens such as viruses and bacteria, the immune system can also become an important ally in enhancing the effect of a therapy. Thanks to the study of the mechanisms underlying different types of immune response, researchers at SR-Tiget are trying to identify strategies to make the therapies developed at the institute even more effective, for example by preventing the immune system from neutralizing the effect or, vice versa, to obtain a synergistic effect against the target (a toxic protein, a tumor, etc.).

The research groups involved are those of: