Primary immunodeficiencies are a group of rare genetic diseases characterized by an altered innate and adaptive immune system, increased susceptibility to infections, risk of autoimmunity and cancer. Adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) is a complex metabolic and immunological disorder, characterized by a severe immunodeficiency due to the accumulation of purine metabolites in plasma and cells. Without treatment, the condition is fatal and requires early intervention. Our studies are at aimed at investigating the molecular and cellular mechanisms linking the purine metabolism disorder to the immune and non immune alterations of the disease. HSR-TIGET was one of the pioneers in bringing gene therapy with retrovirally transduced hematopoietic stem cells from preclinical studies to successful clinical applications. Studies on vector integrations are providing crucial information on vector biology, the dynamics of genetically modified hematopoietic stem cells, and the safety of gene therapy. In addition, we are developing new therapeutic strategies based on the use of lentiviral vectors for ADA-SCID and other primary immunodeficiencies, including Wiskott-Aldrich Syndrome and Chronic Granulomatous Disease. These studies will contribute to improve our knowledge on primary immunodeficiencies and improve patients’ care.