San Raffaele Telethon Institute for Gene Therapy
The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) was created in 1995 as a joint venture between the Telethon Foundation and IRCCS Ospedale San Raffaele, with the mission to perform cutting-edge research in gene and cell therapy and to translate its results into therapeutic advances, focusing on genetic diseases.
Overall, SR-Tiget represents a multi-disciplinary research environment, which provides a unique blend of scientific expertise in the development of innovative gene and cell therapy strategies, access to relevant preclinical models to evaluate their efficacy and safety, as well as competence in conducting early phase clinical trials. This provides a fertile ground for alliances with industrial partners, which possess the skills and resources required to address the regulatory hurdles and manufacturing needs to bring new therapies to registration and make them available to patients.
Research at SR-Tiget spans from basic research to pre-clinical studies to early phase clinical trials according to the following major aims:
- identifying the genetic bases and the pathophysiological processes underlying several types of inherited diseases, including primary immunodeficiencies and autoimmune/autoinflammatory diseases, hematologic diseases, inherited leukodystrophies and other lysosomal storage and neurodegenerative diseases;
- developing novel ex vivo or in vivo gene and cell therapy strategies for such diseases and validating them in ad hoc designed experimental models;
- ameliorating the performance and safety of gene transfer employed for these therapies, i.e. by stringently targeting transduction or expression of lentiviral vectors to the desired cell types and reducing their impact on endogenous transcription at genomic insertion sites;
- characterizing the biological properties of hematopoietic and neural stem and progenitor cells and of mesenchymal stromal cells targeted by these therapies and improving the procedures for their ex vivo isolation, genetic modification and transplantation;
- developing novel technological platforms, including targeted genome and epigenome editing using artificial enzymes with DNA sequence-specific activity (such as ZFN, TALEN and CRISPR-Cas9 nucleases) and scaffolds for ex vivo organoid culture (e.g. for hematopoietic stem cell niche reconstitution);
- investigating the cell types that mediate innate and adaptive immunity, with the aim to develop strategies to induce immunological tolerance to gene and cell products, in order to improve the efficacy and stability of such therapies;
- exploiting the platforms and strategies developed through the abovementioned investigations to design new gene and cell therapies for some common diseases, i.e. to induce tolerance in diabetes and other autoimmune diseases or, conversely, enhance adaptive immunity to cancer associated antigens.
SR-Tiget portfolio of gene and cell therapies now embraces the full spectrum of drug development up to the market. Notably, in May 2016 the European Commission granted marketing authorization for Strimvelis for the treatment of ADA-SCID, a severe form of immunodeficiency. Strimvelis, which is the first approved ex vivo gene therapy worldwide, has been developed at SR-Tiget and brought to the market under a strategic alliance with GSK. The successful results obtained with ADA-SCID provided a rationale for extending the HSC gene therapy approach to other diseases. In particular, two clinical trials for Wiskott-Aldrich Syndrome (WAS) and Metachromatic Leukodystrophy (MLD) started in 2010 and have shown persistent therapeutic benefit in the absence of treatment-related adverse events. A third trial, for beta‐thalassemia, started in 2015 and is showing promising preliminary results. In addition, a trial for Mucopolysaccharidosis type I (MPS-I) is planned to start in 2018.
The CLINICAL RESEARCH Units of SR-Tiget work in close collaboration with the Stem Cell Program and the Pediatric Immuno-Hematology Unit of IRCCS Ospedale San Raffaele.
To foster the development from bench to bedside of the new therapeutic strategies being investigated at SR-Tiget, the following structures have been established in the Institute:
First academic GLP center for performing biodistribution, toxicology/tumorigenicity and validation studies on gene and cell therapy products. The facility was certified by the Italian Ministry of Health in March 2014 and renewed in April 2016.
2. Vector Integration Core
Performs genome-wide profiling of vector integration sites as readout of cell growth at clonal level, in basic research studies and technology development, in preclinical safety studies and in gene therapy treated patients.
3. SR-Tiget clinical Lab
To ensure data integrity and reliability in analyses of samples from clinical trials.
4. Process Development Laboratory (in preparation)
To develop new protocols for vector production, gene editing and ex vivo cell manipulation in a context of GSP (Good Scientific Practices) and Quality by Design.
Clinical research Unit
Epigenetic regulation and targeted genome editing
Gene and neural stem cell therapy for lysosomal storage diseases
Gene transfer into stem cell
Gene transfer technologies and new gene therapy strategies
Genomics of the innate immune system
Human hematopoietic development and disease modeling
Mechanisms of peripheral tolerance
Pathogenesis and treatment of immune and bone diseases
Pathogenesis and therapy of primary immunodeficiencies
Retrovirus-host interactions and innate immunity to gene transfer
Senescence in stem cell aging, differentiation and cancer
Raffaella Di Micco
Translational stem cell and leukemia
Head, Gene transfer technologies and new gene therapy strategies Unit
Head, Pathogenesis and therapy of primary immunodeficiencies Unit
Raffaella Di Micco
Group leader, Senescence in stem cell aging, differentiation and cancer Unit
Group leader, Human hematopoietic development and disease modeling Unit
Head, Gene transfer into stem cell Unit
Group leader, Mechanisms of peripheral tolerance Unit
Group leader, Translational stem cell and leukemia Unit
Head, Gene and neural stem cell therapy for lysosomal storage diseases Unit
Group leader, Epigenetic regulation and targeted genome editing Unit
Group leader, Retrovirus-host interactions and innate immunity to gene transfer Unit
Group leader, Genomics of the innate immune system Unit
Head, Pathogenesis and treatment of immune and bone diseases Unit