San Raffaele Telethon Institute for Gene Therapy
Epigenetic regulation and targeted genome editing
Our Group has pioneered the field of targeted genome editing with artificial nucleases, steadily contributing to its advances for the treatment of human diseases. During these studies, we have also provided experimental frameworks and tools that are now widely adopted by the gene editing community. By capitalizing on these achievements, we have also developed a novel gene silencing modality that exploits epigenetics, rather than genetic inactivation or post-transcriptional down-regulation, to permanently repress genes of therapeutic.
Research activity
Our research efforts revolve around two main areas.
- Targeted Epigenetic Silencing. This wide-encompassing Area is rooted on the epigenetic silencing technology and aims at realizing its full clinical potential, for both inherited and acquired diseases. Although translationally focused, this area foresees several technological improvements, some of which of potential broad relevance in the field of gene therapy.
- Gene discovery. This steadily expanding Area aims at identifying novel players involved in fundamental biological processes, such as epigenetics and gene function in vivo. In the attainment of this goal, it also foresees to disseminate new experimental paradigms and technological advances in the field of genetic screens, the leading technology that will be used here to interrogate, at the genome-scale level and in an unbiased manner, gene function in vitro and in vivo.
Milani M, Annoni A, Bartolaccini S, Biffi M, Russo F, Di Tomaso T, Raimondi A, Lengler J, Holmes MC, Scheiflinger F, Lombardo A, Cantore A, Naldini L. Genome editing for scalable production of alloantigen-free lentiviral vectors for in vivo gene therapy. EMBO Molecular Medicine. 2017 Nov;9(11):1558-1573.
Schiroli G, Ferrari S, Conway A, Jacob A, Capo V, Albano L, Plati T, Castiello MC, Sanvito F, Gennery AR, Bovolenta C, Palchaudhuri R, Scadden DT, Holmes MC, Villa A, Sitia G, Lombardo A, Genovese P, Naldini L. Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1. Science Translational Medicine. 2017 Oct 11;9(411).
Amabile A, Migliara A, Capasso P, Biffi M, Naldini L, Lombardo A. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell. 2016 Sep 22;167(1):219-232.e14.
Lombardo A & Naldini L. Genome Editing: A tool for research and therapy: targeted genome editing hits the clinic. Nature Medicine. 2014 Oct 8;20(10):1101-3.
P, Schiroli G, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC, Gregory PD, van der Burg M, Gentner B, Montini E, Lombardo A, Naldini L. Targeted genome editing in human repopulating hematopoietic stem cells. Nature. 2014 Jun 12;510(7504):235-40.
Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ, Reik A, Chu V, Paschon DE, Zhang L, Kuball J, Camisa B, Bondanza A, Casorati G, Ponzoni M, Ciceri F, Bordignon C, Greenberg PD, Holmes MC, Gregory PD, Naldini L, Bonini C. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nature Medicine 2012 May;18(5):807-15
Lombardo A, Cesana D, Genovese P, Di Stefano B, Provasi E, Colombo DF, Neri M, Magnani Z, Cantore A, Lo Riso P, Damo M, Pello OM, Holmes MC, Gregory PD, Gritti A, Broccoli V, Bonini C, Naldini L. Site-specific integration and tailoring of cassette design for sustainable gene transfer. Nature Methods 2011 Aug 21;8(10):861-9.
Gabriel R, Lombardo A, Arens A, Miller JC, Genovese P, Kaeppel C, Nowrouzi A, Bartholomae CC, Wang J, Friedman G, Holmes MC, Gregory PD, Glimm H,
Schmidt M, Naldini L, von Kalle C. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nature Biotechnology 2011 Aug 7;29(9):816-23.
Lombardo A, Genovese P, Beausejour CM, Colleoni S, Lee YL, Kim KA, Ando D, Urnov FD, Galli C, Gregory PD, Holmes MC, Naldini L. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nature Biotechnology 2007 Nov;25(11):1298-306.
