The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)

ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of ADA SCID

PI: Alessandro Aiuti; Co-PI: Maria Grazia Roncarolo, Fabio Ciceri

ADA-SCID is an autosomal recessive form of Severe Combined Immunodeficiency (SCID) characterized by impaired immune responses, recurrent infections, failure to thrive and systemic toxicity due to accumulation of purine metabolites. Transplants from an HLA-identical sibling donor is the treatment of choice, but available for a minority of patients. The use of alternative bone marrow donors or enzyme replacement therapy is associated with important drawbacks. SR-Tiget has pioneered the successful gene therapy clinical trial for ADA-SCID. This clinical trial, now completed, introduced a conditioning regimen to favor the engraftment of gene corrected cells and is considered to be among the most important clinical result of gene therapy for genetic diseases. The experimental medicinal product, consisting of autologous CD34+ hematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding ADA, has been designated as Orphan Drug in Europe and USA.

A phase I/II protocol has been conducted at SR-Tiget since 2002, to evaluate the safety and efficacy of ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of adenosine deaminase (ADA)-deficiency. The engineered CD34+ cells were infused following a nonmyeloablative conditioning with busulfan to make space in the bone marrow. The study objectives were: a) to evaluate the safety and the clinical efficacy of gene therapy, in the absence of enzyme replacement therapy; b) to evaluate the biological activity (engraftment, ADA expression) of ADA transduced CD34+ cells and their hematopoietic progeny; c) to evaluate the immunological reconstitution and purine metabolism after gene therapy. The clinical trial has enrolled 12 patients and 3 other patients have been treated under pilot program and 3 under compassionate use. The first reports published in 2002 (Aiuti et al. Science) and 2009 (Aiuti et al., N Engl J Med) showed long-term engraftment of multilineage gene corrected progenitor, improved T-cell counts and functions, sustained metabolic detoxification, with substantial clinical benefit and no adverse events related to gene therapy. Currently all patients are alive, with the longest follow at >12 years, and no evidence of clonal abnormalities. On October 2010 SR-Tiget entered a strategic alliance with GlaxoSmithKline (GSK), which took exclusive rights to commercialise ADA-SCID gene therapy, committing to further develop product manufacturing to make therapy available to patients. NCT00598481


Selected publications

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 MG, Bordignon C. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002. 296, 2410-2413.

Aiuti A, Vai S, Mortellaro A, Casorati G, Ficara F, Andolfi G, Ferrari G, Tabucchi A, Carlucci F, Ochs HD, Notarangelo LD, Roncarolo MG, Bordignon C. Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med. 2002. 8, 423-425.

Carlucci F, Tabucchi A, Aiuti A, Rosi F, Floccari F, Pagani R, Marinello E. Capillary electrophoresis in diagnosis and monitoring of adenosine deaminase deficiency. Clin Chem. 2003. 49, 1830-1838.

Ficara F, Superchi DB, Hernandez RJ, Mocchetti C, Carballido-Perrig N, Andolfi G, Deola S, Colombo A, Bordignon C, Carballido JM, Roncarolo MG, Aiuti A. IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential. Mol Ther. 2004. 10, 1096-1108.

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.

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 L, 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, 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.

Cancrini C, Ferrua F, Scarselli A, Brigida I, Romiti ML, Barera G, Finocchi A, Roncarolo MG, Caniglia M, Aiuti A. Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID. Haematologica. 2010. 95, 1778-1782.

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.

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

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.

Hassan A, Booth C, Brightwell A, Allwood Z, Veys P, Rao K, Hoenig M, Friedrich W, Gennery AR, Slatter M, Bredius R, Finocchi A, Cancrini C, Aiuti A, Lanfranchi A, Porta F, Ridella M, Graham 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 Zaharani D, Roifman C, Boelens JJ, Davies EG, Cavazzana-Calvo M, Notarangelo L, Gaspar HB. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012 Jul 12 [Epub ahead of print].

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.