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.

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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.

Selected publications

Scala S, Ferrua F, Basso-Ricci L, Dionisio F, Omrani M, Quaranta P, Jofra Hernandez R, Del Core L, Benedicenti F, Monti I, Giannelli S, Fraschetta F, Darin S, Albertazzi E, Galimberti, Montini E, Calabria A, Cicalese MP & Aiuti A. Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy Nat Commun. 2023 May 27;14(1):3068. doi: 10.1038/s41467-023-38448-y

Aiuti A., Slavin S., Aker M., Ficara F., Deola S., Mortellaro A., Morecki S., Andolfi G., Tabucchi A., Carlucci F., Marinello E., Cattaneo F., Vai S., Servida P., Miniero R., Roncarolo M. G., and Bordignon C (2002). Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science (New York, NY) 296, 2410-2413.

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 L., Wintergerst U., Buckley R.H., Bregni M., Marktel S., Valsecchi M.G., Rossi P., Ciceri, F. Miniero R., Bordignon C., and Roncarolo M.G (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360, 447-458.

Brigida I., Zoccolillo M., Cicalese M.P., Pfajfer L., Barzaghi F., Serena Scala S., Oleaga-Quintas C., Alvarez J.A., Sereni L., Giannelli S., Sartirana C., Dionisio F., Pavesi L., Benavides-Nieto M., Basso-Ricci L., Capasso P., Mazzi B., Rosain J., Marcus N., Lee Y.N., Somech R., Degano M., Raiola G., Caorsi R, Picco P., Moncada Velez M., Khourieh J., Arias A.A., Bousfiha A., Issekutz T., Issekutz A., Boisson B., Kerry Dobbs K., Anna Villa A., Lombardo A., Neven B., Moshous D., Casanova J.L., Franco J.L., Notarangelo L.D., Scielzo C., Volpi S., Dupré L., Bustamante J., Gattorno M., and Aiuti A. (2018). T cell defects in patients with ARPC1B germline mutations account for their combined immunodeficiency. Blood. 132:2362-2374..

Scala S., Basso-Ricci L., Dionisio F., Pellin D., Giannelli S., Salerio F.A., Leonardelli L., Cicalese M.P., Ferrua F., Aiuti A.*, and Biasco L.*(2018). Dynamics of hematopoietic stem/progenitor cells after autologous transplantation in humans. Nat Med. 24:1683-1690. * Equal author contribution

Ferrua F.*, Cicalese M.P.*, Galimberti S., Giannelli S., Dionisio F., Barzaghi F., Migliavacca M., Bernardo M.E., Calbi V., Assanelli A.A., Facchini M., Fossati C., Albertazzi E., Scaramuzza S., Brigida I., Scala S., Basso-Ricci L., Pajno R., Casiraghi M., Canarutto D., Salerio F. A., Albert M. H., Bartoli A., Wolf H.M., Fiori R., Silvani P., Gattillo S., Villa A., Biasco L., Dott C., Culme-Seymour E.J., van Rossem K., Atkinson G., Valsecchi M.G., Roncarolo M.G., Ciceri F., Naldini L., and Aiuti A. (2019) . Lentiviral haematopoietic stem/progenitor cell gene therapy for the treatment of Wiskott-Aldrich syndrome: interim results of a non-randomized, open-label, phase 1/2 clinical study. Lancet Hematology. 6: e239-e253.

Cifaldi C.*, Brigida I.*, Barzaghi F.*, Zoccolillo M., Ferradini V., Petricone D., Cicalese M.P., Lazarevic D., Cittaro D., Omrani M., Attardi E., Conti F., Scarselli A., Chiriaco M., Di Cesare S., Licciardi F., Davide M., Ferrua F., Canessa C., Pignata C., Giliani S., Ferrari S., Fousteri G., Barera G., Merli P., Palma P., Cesaro S., Gattorno M., Trizzino A., Moschese V., Chini L., Villa A., Azzari C., Finocchi A., Locatelli F., Rossi P., Sangiuolo F., Aiuti A. @, Cancrini C. @*, and Di Matteo G*. (2019). Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies. Front Immunol. 10:316.

Jofra Hernández R., Calabria A., Sanvito F., De Mattia F., Farinelli G., Scala S., Visigalli I., Carriglio N., De Simone M., Vezzoli M., Cecere F., Migliavacca M., Basso-Ricci L., Omrani M., Benedicenti F., Norata R., Rancoita P.M.V., Di Serio C., Albertini P., Cristofori P., Naldini L., Gentner B., Montini E., Aiuti A.@, and Mortellaro A. (2021). Hematopoietic Tumors in a Mouse Model of X-linked Chronic Granulomatous Disease after Lentiviral Vector-Mediated Gene Therapy. Mol Ther. 29: 86-102.

Ferrari G., Thrasher A.J., and Aiuti A. (2021). Gene therapy using haematopoietic stem and progenitor cells. Nat Rev Genet. 22: 216-234.

Gentner B., Tucci F., Galimberti S., Fumagalli F., De Pellegrin M., Silvani P., Camesasca C., Pontesilli S., Darin S., Ciotti F., Sarzana M., Consiglieri G., Filisetti C., Forni G., Passerini L., Tomasoni D., Cesana D., Calabria A., Spinozzi G., Cicalese M.P., Calbi V., Migliavacca M., Barzaghi F., Ferrua F., Gallo V., Miglietta S., Zonari E., Cheruku P.S., Forni C., Facchini M., Corti A., Gabaldo M., Zancan S., Gasperini S., Rovelli A., Boelens J.J., Jones S.A., Wynn R., Baldoli C., Montini E., Gregori S., Ciceri F., Valsecchi M.G., la Marca G., Parini R., Naldini L., Aiuti A*., Bernardo M.E*. and MPSI Study Group. (2021). Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. N Engl J Med. 385:1929-1940. ¶ corresponding author

Basso-Ricci L, Scala S, Milani R, Migliavacca M, Rovelli A, Bernardo ME, Ciceri F, Aiuti A, Biasco L. Multiparametric Whole Blood Dissection: A one-shot comprehensive picture of the human hematopoietic system. Cytometry A. 2017 Oct;91(10):952-965.

Biasco L, Pellin D, Scala S, Dionisio F, Basso-Ricci L, Leonardelli L, Scaramuzza S, Baricordi C, Ferrua F, Cicalese MP, Giannelli S, Neduva V, Dow DJ, Schmidt M, Von Kalle C, Roncarolo MG, Ciceri F, Vicard P, Wit E, Di Serio C, Naldini L, Aiuti A. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution Phases. Cell Stem Cell 2016 Jul 7;19(1):107-19.

Biasco L, Scala S, Basso Ricci L, Dionisio F, Baricordi C, Calabria A, Giannelli S, Cieri N, Barzaghi F, Pajno R, Al-Mousa H, Scarselli A, Cancrini C, Bordignon C, Roncarolo MG, Montini E, Bonini C, Aiuti A. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med. 2015 Feb 4;7(273):273ra13.

Chiriaco M, Farinelli G, Capo V, Zonari E, Scaramuzza S, Di Matteo G, Sergi LS, Migliavacca M, Hernandez RJ, Bombelli F, Giorda E, Kajaste-Rudnitski A, Trono D, Grez M, Rossi P, Finocchi A, Naldini L, Gentner B, Aiuti A. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis. Mol Ther. 2014 Aug;22(8):1472-1483.

Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 2013 Aug 23;341(6148):1233151.