San Raffaele Telethon Institute for Gene Therapy
Pathogenesis and treatment of immune and bone diseases
Our work is focused on the pathophysiology and development of novel cellular therapies to cure severe combined immunodeficiencies caused by RAG genes and inherited bone defects due to osteoclast dysfunction.
Research activity
Genetic mutations in RAG genes cause a broad spectrum of clinical manifestations including T- B- SCID, Omenn syndrome, atypical SCID and combined immunodeficiency with granuloma/autoimmunity (CID-G/AI). The main goal of our research is to develop a platform to treat RAG1 defect by exploiting gene editing approach in hematopoietic stem and progenitor cells (HSPC) carrying null or hypomorphic RAG defects and testing novel conditioning regimen based on the use of biological compounds to preserve tissue integrity.
In parallel to cure Autosomal Recessive Osteopetrosis (ARO) caused by defects in osteoclast function, we have optimized a novel platform of gene therapy coupling lentiviral gene transduction with HSPC expansion. We plan to dissect the molecular and cellular heterogeneity of hematopoietic stem and progenitor cells spontaneously circulating in the peripheral blood of ARO patients and evaluate the effect of repeated infections on hematopoietic stem cell stemness and quiescence.
Penna S, Villa A, Capo V. Autosomal recessive osteopetrosis: mechanisms and treatments. Dis Model Mech. 2021 May 1;14(5):dmm048940. doi: 10.1242/dmm.048940. Epub 2021 May 10
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.
Villa A, Capo V, Castiello MC. Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency. Front Immunol. 2020 Nov 19;11:607926. doi: 10.3389/fimmu.2020.607926. eCollection 2020.
Castiello MC, Bosticardo M, Sacchetti N, Calzoni E, Fontana E, Yamazaki Y, Draghici E, Corsino C, Bortolomai I, Sereni L, Yu HH, Uva P, Palchaudhuri R, Scadden DT, Villa A, Notarangelo LD. Efficacy and safety of anti-CD45-Saporin as conditioning agent for RAG deficiency. J Allergy Clin Immunol. 2020 May 5:S0091-6749(20)30629-1. doi: 10.1016/j.jaci.2020.04.033. Online ahead of print. PMID: 32387109
Rigoni R, Fontana E, Dobbs K, Marrella V, Taverniti V, Maina V, Facoetti A, D'Amico G, Al-Herz W, Cruz-Munoz ME, Schuetz C, Gennery AR, Garabedian EK, Giliani S, Draper D, Dbaibo G, Geha RS, Meyts I, Tousseyn T, Neven B, Moshous D, Fischer A, Schulz A, Finocchi A, Kuhns DB, Fink DL, Lionakis MS, Swamydas M, Guglielmetti S, Alejo J, Myles IA, Pittaluga S, Notarangelo LD, Villa A*, Cassani B*. Cutaneous Barrier Leakage and Gut Inflammation Drive Skin Disease in Omenn Syndrome. J Allergy Clin Immunol. 2020 Apr 17; S0091-6749(20)30492-9. doi: 10.1016/j.jaci.2020.04.005.
Villa A, Notarangelo LD. RAG gene defects at the verge of immunodeficiency and immune dysregulation Immunol Rev. 2019 Jan;287(1):73-90. doi: 10.1111/imr.12713. Review.
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.
