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Pathogenesis and therapy of primary immunodeficiencies

SR-Tiget Unit
Alessandro Aiuti, Clinical Research Coordinator and Head of Unit

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 aimed at investigating the molecular and cellular mechanisms linking the purine metabolism disorder to the immune and non-immune alterations of the disease. SR-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.

Selected publications


Cassani B, Mirolo M, Cattaneo F, Benninghoff U, Hershfield M, Carlucci F, Tabucchi A, Bordignon C, Roncarolo MG, Aiuti A. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood. 2008. 111, 4209-19.

Aiuti A, Brigida I, Ferrua F, Cappelli B, Chiesa R, Marktel S, Roncarolo MG. Hematopoietic stem cell gene therapy for adenosine deaminase deficient-SCID. Immunol Res. 2009. 44, 150-9.

Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo LD, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009. 360, 447-58.

Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS,  Notarangelo LD.  How I treat ADA deficiency. Blood. 2009. 114, 3524-3532.

Sauer AV, Brigida I, Carriglio N, Jofra Hernandez R, Scaramuzza S, Clavenna D, Sanvito F, Poliani PL, Gagliani N, Carlucci F, Tabucchi A, Roncarolo MG, Traggiai E, Villa A, Aiuti A. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood. 2011. 119, 1428-39.

Sauer AV, Morbach H, Brigida I, Ng YS, Aiuti A, Meffre E. Defective B cell tolerance due to adenosine deaminase deficiency is corrected by gene therapy. J Clin Invest. 2012. 122, 2141-52.

Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, Aiuti A. Gene therapy for primary immunodeficiencies: Part 1. Curr Opin Immunol. 2012. 24,1-5.

Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012. 3, 265.

Brigida I, Sauer AV, Ferrua F, Giannelli S, Scaramuzza S, Pistoia V, Castiello MC, Barendregt BH, Cicalese MP, Casiraghi M, Brombin C, Puck J, Müller K, Notarangelo LD, Montin D, van Montfrans JM, Roncarolo MG, Traggiai E, van Dongen JJ, van der Burg M, Aiuti A. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients. J Allergy Clin Immunol. 2014. 133(3):799-806.e10.


Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, Grunebaum E, Roifman CM, Cervi MC, Ambrosi A, Carlucci F, Roncarolo MG, Villa A, Rubinacci A,  Aiuti A. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood. 2009. 114, 3216-3226.

Sauer AV, Aiuti A. New insights into the pathogenesis of adenosine deaminase-severe combined immunodeficiency and progress in gene therapy. Curr Opin Allergy Clin Immunol. 2009. 9, 496-502. IF 3.497.

Ferrua F, Brigida I, Aiuti A. Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. Curr Opin Allergy Clin Immunol. 2010. Epub 10, 551-556.

Hassan A, Booth C, Brightwell A, Allwood Z, Veys P, Rao K, Hönig M, Friedrich W, Gennery A, Slatter M, Bredius R, Finocchi A, Cancrini C, Aiuti A, Porta F, Lanfranchi A, Ridella M, Steward C, Filipovich A, Marsh R, Bordon V, Al-Muhsen S, Al-Mousa H, Alsum Z, Al-Dhekri H, Al Ghonaium A, Speckmann C, Fischer A, Mahlaoui N, Nichols KE, Grunebaum E, Al Zahrani D, Roifman CM, Boelens J, Davies EG, Cavazzana-Calvo M, Notarangelo L, Gaspar HB; Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and European Society for Immunodeficiency. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012. 120(17):3615-24.


Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C.  Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007. 117, 2233-2240.

Cattoglio C, Facchini G, Sartori D, Antonelli A, Miccio A, Cassani B, Schmidt M, von Kalle C, Howe S, Thrasher AJ, Aiuti A, Ferrari G, Recchia A, Mavilio F. Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood. 2007. 110, 1770-1778.

Cassani B, Montini E, Maruggi G, Ambrosi A, Mirolo M, Selleri S, Biral E, Frugnoli I, Hernandez-Trujillo V, Di Serio C, Roncarolo MG, Naldini L, Mavilio F, Aiuti A.  Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Blood. 2009. 114, 3546-3556.

Gabriel R, Eckenberg R, Paruzynski A, Bartholomae CC, Nowrouzi A, Arens A, Howe SJ, Recchia A, Cattoglio C, Wang W, Faber K, Schwarzwaelder K, Kirsten R, Deichmann A, Ball CR, Balaggan KS, Yanez-Munoz RJ, Ali RR, Gaspar H B, Biasco L, Aiuti A, Cesana D, Montini E, Naldini L, Cohen-Haguenauer O, Mavilio F, Thrasher AJ, Glimm H, von Kalle C, Saurin W, Schmidt M.  Comprehensive genomic access to vector integration in clinical gene therapy. Nat Med. 2009. 15, 1431-1436.

Biasco L, Ambrosi A, Pellin D, Bartholomae C, Brigida I, Roncarolo MG, Di Serio C, von Kalle C, Schmidt M, Aiuti A. Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell. EMBO Mol Med. 2010. 3, 89-101.

Selleri S, Brigida I, Casiraghi M, Scaramuzza S, Cappelli B, Cassani B, Ferrua F, Aker M, Slavin S, Scarselli A, Cancrini C, Marktel S, Roncarolo MG, Aiuti A. In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency. J Allergy Clin Immunol. 2011. 127, 1368-1375.

Deichmann A, Brugman MH, Bartholomae CC, Schwarzwaelder K, Verstegen MM, Howe SJ, Arens A, Ott MG, Hoelzer D, Seger R, Grez M, Hacein-Bey-Abina S, Cavazzana-Calvo M, Fischer A, Paruzynski A, Gabriel R, Glimm H, Abel U, Cattoglio C, Mavilio F, Cassani B, Aiuti A, Dunbar CE, Baum C, Gaspar HB, Thrasher AJ, von Kalle C, Schmidt M, Wagemaker G. Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy. Mol Ther. 2011. 19, 2031-9.

Biasco L, Baricordi C, Aiuti A. Retroviral integrations in gene therapy trials. Mol. Ther. 2012. 20, 709-16.


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