San Raffaele Telethon Institute for Gene Therapy
Pathogenesis and treatment of immune and bone diseases
To dissect mechanisms underlying autoimmunity, this Unit studies genetic defects characterised by infections and autoimmunity. Different diseases ranging from defects in RAG molecules or in genes involved in actin cytoskeleton remodelling (Wiskott-Aldrich syndrome, WAS) or defects associated with thymic abnormalities, are the main topics of the lab.
Research activity
The group is focused on the contribution of defective thymic cross-talk to the pathogenesis of autoimmunity in various diseases and how emerging regenerative therapies may remodel thymic architecture and T cell development. To this end, the combination of cell/gene therapy and regenerative medicine represents an innovative therapeutic approach to treat primary and secondary thymic defects.
Immunedysregulation and platelet defect will be studied in WAS with the final aim to dissect the contribution of B and Platelets to the pathogenesis of the disease. To this end, researchers are evaluating the efficacy of LV-mediated gene therapy (GT) currently ongoing at SR-Tiget.
Finally, studies are ongoing to evaluate the feasibility and efficacy of lentiviral mediated gene therapy of a severe bone defect due to alterations in osteoclast function. Autosomal recessive osteopetrosis (ARO) is caused by mutations in genes involved in the differentiation or resorption activity of osteoclasts, leading to death in the first decade of life. Lentiviral vector gene therapy is under development as alternative strategy, relying on peripheral blood (PB) CD34+ cells as the source of autologous hematopoietic stem and progenitor cells (HSPC). This group has developed a lentiviral platform that will be tested in the spontaneous mouse model, the oc/oc mouse and in CD34+ cells obtained from patients. These studies will be performed in parallel with analysis of the roles played by osteoclasts in the bone marrow niche.
Immunedysregulation and platelet defect will be studied in WAS with the final aim to dissect the contribution of B and Platelets to the pathogenesis of the disease. To this end, researchers are evaluating the efficacy of LV-mediated gene therapy (GT) currently ongoing at SR-Tiget.
Finally, studies are ongoing to evaluate the feasibility and efficacy of lentiviral mediated gene therapy of a severe bone defect due to alterations in osteoclast function. Autosomal recessive osteopetrosis (ARO) is caused by mutations in genes involved in the differentiation or resorption activity of osteoclasts, leading to death in the first decade of life. Lentiviral vector gene therapy is under development as alternative strategy, relying on peripheral blood (PB) CD34+ cells as the source of autologous hematopoietic stem and progenitor cells (HSPC). This group has developed a lentiviral platform that will be tested in the spontaneous mouse model, the oc/oc mouse and in CD34+ cells obtained from patients. These studies will be performed in parallel with analysis of the roles played by osteoclasts in the bone marrow niche.
Capo V, Penna S, Merelli I, Barcella M, Scala S, Basso-Ricci L, Draghici E, Palagano E, Zonari E, Desantis G, Uva P, Cusano R, Sergi Sergi L, Crisafulli L, Moshous D, Stepensky P, Drabko K, Kaya Z, Unal E, Gezdirici A, Menna G, Serafini M, Aiuti A, Locatelli SL, Carlo-Stella C, Schulz AS, Ficara F, Sobacchi C, Gentner B, Villa A. Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis. Haematologica. 2020 Jan 16. pii: haematol.2019.238261. doi: 10.3324/haematol.2019.238261.
Sereni L, Castiello MC, Di Silvestre D, Della Valle P, Brombin C, Ferrua F, Cicalese MP, Pozzi L, Migliavacca M, Bernardo ME, Pignata C, Farah R, Notarangelo LD, Marcus N, Cattaneo L, Spinelli M, Giannelli S, Bosticardo M, van Rossem K, D'Angelo A, Aiuti A, Mauri P, Villa A. Lentiviral gene therapy corrects platelet phenotype and function in Wiskott-Aldrich patients J Allergy Clin Immunol. 2019 Sep;144(3):825-838. doi: 10.1016/j.jaci.2019.03.012. Epub 2019 Mar 27.
Sereni L, Castiello MC, Marangoni F, Anselmo A, di Silvestre D, Motta S, Draghici E, Mantero S, Thrasher AJ, Giliani S, Aiuti A, Mauri P, Notarangelo LD, Bosticardo M, Villa A. Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation. J Allergy Clin Immunol. 2018 Oct;142(4):1272-1284. doi: 10.1016/j.jaci.2017.12.1000. Epub 2018 Feb 6
Capo V, Castiello MC, Fontana E, Penna S, Bosticardo M, Draghici E, Poliani LP, Sergi Sergi L, Rigoni R, Cassani B, Zanussi M, Carrera P, Uva P, Dobbs K, Sacchetti N, Notarangelo LD, van Til NP, Wagemaker G, Villa A. Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation. J Allergy Clin Immunol. 2018 Sep;142(3):928-941.e8. doi: 10.1016/j.jaci.2017.11.015. Epub 2017 Dec 11.
Sereni L, Castiello MC, Villa A. Platelets in Wiskott-Aldrich syndrome: victims or executioners? J Leukoc Biol. 2018 Mar;103(3):577-590.
Castiello MC, Pala F, Sereni L, Draghici E, Inverso D, Sauer AV, Schena F, Fontana E, Radaelli E, Uva P, Cervantes-Luevano KE, Benvenuti F, Poliani PL, Iannacone M, Traggiai E, Villa A, Bosticardo M. In vivo chronic stimulation unveils autoreactive potential of Wiskott-Aldrich syndrome protein-deficient B cells. Front Immunol. 2017 May 2;8:490.
Rigoni R, Grassi F, Villa A, Cassani B. RAGs and BUGS: An alliance for autoimmunity. Gut Microbes 2016 Nov;7(6):503-511.
Rigoni R, Fontana E, Guglielmetti S, Fosso B, D’Erchia A.M, Maina V , Taverniti V, Castiello M.C, Mantero S, Pacchiana G, Musio S, Pedotti R, Mora J.R , Pesole G, Vezzoni P, Poliani LP, F. Grassi F, Villa A*, Cassani B. Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. J Exp Med. 2016 Mar 7;213(3):355-75. *corresponding author.
Pala F, Morbach H, Castiello MC, Schickel JN, Scaramuzza S, Chamberlain N, Cassani B, Glauzy S, Romberg N, Candotti F, Aiuti A, Bosticardo M, Villa A*, Meffre E*. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott- Aldrich syndrome patients. J Clin Invest. 125(10):3941-51,2015. * co-senior author.
Castiello MC, Scaramuzza S, Pala F, Ferrua F, Uva P, Brigida I, Sereni L, van der Burg M, Ottaviano G, Albert MH, Roncarolo MG, Naldini L, Aiuti A, Villa A, Bosticardo M. B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2015 Sep;136(3):692-702.e2.
