Epigenetic regulation and targeted genome editing
This Group is interested in developing innovative approaches to treat diseases and to study fundamental biological questions. To this end, we recently developed a novel strategy to permanently silence gene expression through targeted epigenetic editing. We are exploiting this innovate strategy to: (i) tackle inherited diseases for which gene silencing is a valid therapeutic solution, such as hemoglobinopathies and familial hypercholesterolemia; (ii) determine the specificity and persistence of epigenetic silencing across cell development and differentiation, two key aspects for effective and safe exploitation of the technology; (iii) shed light into the fundamental principles governing establishment and maintenance of epigenetic silencing, basic biological information that can potentially be used to further improve the platform.
To accomplish these goals, we are taking advantage of stealth and effective gene delivery procedures, relevant disease models, genome-scale loss-of-function and single-cell transcriptomic analyses, in collaborations with internationally renowned scientists. Finally, building on our extensive experience in targeted genome editing, we are now expanding our field of research to include cell and organ transplantation. To this end, we are:
- coupling state-of-the-art gene editing and cell reprogramming procedures to generate off-the-shelf immunocompatible allogeneic cells for tissue transplantation;
- harnessing the differentiation potential of pluripotent stem cells to derive interspecies chimera with potential clinical applications.
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.