San Raffaele Telethon Institute for Gene Therapy

Pathogenesis and therapy of primary immunodeficiencies


Head of Unit

Alessandro Aiuti


Hematopoietic stem/progenitor cells (HSPCs) represent a new therapy class of “living medicine” aimed at preventing and/or correcting genetic diseases of the blood and other tissues. HSPC gene therapy (GT) is based on infusion of gene-modified hematopoietic stem cells collected from bone marrow or mobilized peripheral blood of patients. Few circulating HSPCs can also be found in peripheral blood but their role and the molecular mechanisms responsible for their re-circulation is poorly understood.

SR-Tiget was one of the pioneer Institute bringing HSPC GT from preclinical studies to successful clinical applications, up to the first 2 approved medicinal products in the EU. In particular, our group treated with HSPC GT more than 120 patients affected by several genetic diseases including primary immunodeficiencies (such as Adenosine deaminase deficiency and Wiskott-Aldrich Syndrome), and metabolic disorders (such as Metachromatic leukodystrophy and Mucopolysaccharidosis type I). Without treatment, many of these conditions are fatal and require early intervention.

Research activity

Our group has the main research focus of studying the properties, dynamics and biology of human hematopoietic stem cells (HSCs) at steady-state and after infusion into the patients, with the aim of improving the current HSPC GT strategies. We previously demonstrated that hematopoietic reconstitution after GT occurs in distinct multi-clonal waves, with gene corrected HSCs representing a major contributor to steady state hematopoiesis. Our goals are to dissect: a) the molecular mechanisms responsible for physiological trafficking and drug-induced mobilization; b) the functional properties of circulating hematopoietic stem cells, with the aim of exploiting them as new source for hematopoietic stem cell gene therapy; c) the characteristics of the engrafted hematopoietic stem cells long term (> 8 years) after infusion.

To these aims, we combine multiple approaches including phenotypic characterization, transcriptome profiling, functional assays and tracking each single HSC and its progeny directly into the patients thanks to the concept that, upon gene-correction, each stem cell becomes molecularly marked by distinct insertion sites, where the therapeutic vector integrated into the DNA of the patients’ cells. Collectively, these studies will allow to increase our knowledge on the HSC biology ultimately leading to improved gene therapy strategies and to extend this type of treatment to other diseases.

Moreover, our group is involved in the pre-clinical development of lentiviral-based gene therapy approaches for the treatment of immunodeficiencies and lysosomal storage disorders and collaborates with international networks in studying the bases of congenital immune deficiencies.