Luigi Naldini

Tecnologie di trasferimento genico e nuove strategie di terapia genica

Unità SR-Tiget - ERC Advanced Grant
Luigi Naldini, Capo Unità

luigi.naldini@hsr.it

La terapia genica affronta la malattia genetica alla sua base in quanto mira a contrastare o a ripristinare nella cellula affetta la funzione di un gene “difettoso” mediante il trasferimento di una versione corretta e funzionale dello stesso gene o di un suo antagonista. Per realizzare questi obiettivi ambiziosi servono strumenti efficaci per il trasferimento genico, spesso derivati da virus modificati e resi innocui in laboratorio. I virus modificati (vettori virali) entrano nelle cellule bersaglio come se fossero virus naturali, ma invece di trasportare i propri geni introducono il gene terapeutico. La ricerca svolta nel nostro laboratorio ha messo a punto un sistema per trasferire efficientemente e stabilmente geni anche in cellule particolarmente refrattarie ai metodi convenzionali.

Pubblicazioni selezionate

IMPROVING HEMATOPOIETIC STEM CELL GENE THERAPY AND REGULATED VECTORS

Biffi A*, Montini E*, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta N, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow JD, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M and Naldini L. Therapeutic Benefit in Metachromatic Leukodystrophy by Lentiviral Hematopoietic Stem Cell Gene Therapy. Science. 2013 Aug 23;341(6148): 1233158. Epub 2013 Jul 11.
* These authors contributed equally to this work.
Featured in: Perspective: Verma I. Science 2013 Aug 23; 341(6148):853-5. News & Views: Leboulch P. Nature 2013 Aug 15; 500(7462):280-2. Previews: Williams D.A. Cell Stem Cell 2013 Sep 5; 263-264 Research Highlights: the Editor, Molecular Therapy Aug 23;21(8):1469.  Times Cited: 3

Aiuti A, Biasco L§, Scaramuzza S§, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee P, Orange J, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG‡, Naldini L‡. Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome. Science. 2013 Aug 23; 341(6148): 1233151. Epub 2013 Jul 11.
§Equal second author contribution
‡These authors contributed equally to this work
Featured in: Perspective: Verma I. Science 2013 Aug 23;341(6148):853-5. News & Views: Leboulch P. Nature 2013 Aug 15;  500(7462):280-2. Previews: Williams D.A. Cell Stem Cell 2013 Sep 5; 263-264. Research Highlights: the Editor, Molecular Therapy Aug 23;21(8):1469

Santoni de Sio FR, Cascio P, Zingale A, Gasparini M,  Naldini L. Proteasome Activity Restricts Lentiviral Gene Transfer in Hematopoietic Stem Cells and is Down-Regulated by Cytokines that Enhance Transduction. Blood. 2006. 107(11):4257-65. Times cited: 32

Brown BD*, Gentner B*, Cantore A, Colleoni S, Amendola M, Zingale A, Baccarini A, Lazzari G, Galli C, Naldini L. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotechnology. 2007. 25(12):1457-1467.Epub 2007 Nov.16. (*Co-first authors: BDB, BG). Times cited:157

Santoni de Sio FR, Gritti A, Cascio P, Neri M, Sampaolesi M, Galli C, Luban J, Naldini L. Lentiviral Vector Gene Transfer is limited by the proteasome at post-entry steps in various Types of Stem Cells. Stem Cells. 2008. 26(8):2142-52. Epub 2008 May 15. Times cited:16

Gentner B*, Visigalli I*, Hiramatsu H*, Lechman ER*, Ungari S, Giustacchini A, Schira G, Amendola M, Quattrini A, Martino S, Orlacchio A, Dick J, Biffi A, Naldini L. Identification of Hematopoietic Stem Cell-Specific miRNAs Enables Gene Therapy of Globoid Leukodystrophy. Science Translational Medicine. 2010. 2(58):58ra84. *Co-first authors: BG, IV, HH, ERL. Co-senior and corresponding authors: AB and LN. Featured in: Commentary: Burgess. Nat Rev Genet. 2011 Jan;12(1):4.

Brown BD, Naldini L. Exploiting and antagonizing miRNA regulation for therapeutic and experimental applications. Nature Reviews Genetics. 2009. 10(8):578-85. Times cited:115

Naldini L. Ex vivo gene transfer and correction for cell-based therapies. Nature Reviews Genetics. 2011. 12(5):301-15. Epub 2011 Mar 29. Times cited: 43

Gentner B, Naldini L. Exploiting microRNA regulation for genetic engineering. Tissue Antigens. 2012. 80(5):393-403. doi: 10.1111/tan.12002.

INVESTIGATING microRNA BIOLOGY IN THE HEMATOPOIETIC SYSTEM

Amendola M, Venneri MA, Biffi A, Vigna E, Naldini L. Coordinate dual-gene transgenesis by Lentiviral Vectors Carrying Synthetic Bidirectional Promoters. Nature Biotechnology. 2005. 23(1):108-16. Times cited:123

Brown BD*, Gentner B*, Cantore A, Colleoni S, Amendola M, Zingale A, Baccarini A, Lazzari G, Galli C, Naldini L. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotechnology. 2007. 25(12):1457-1467. Epub 2007 Nov.16.*Co-first authors: BDB, BG. Times cited:157

Amendola M, Passerini L, Pucci F, Gentner B, Bacchetta R, Naldini L. Regulated and Multiple miRNA and siRNA Delivery into Primary Cells by a Lentiviral Platform. Molecular Therapy. 2009. 17(6):1039-52. Epub 2009 Mar 17. Times cited:19

Gentner B, Schira G, Giustacchini A, Amendola M, Brown BD, Ponzoni M, Naldini L. Stable Knockdown of microRNA in Vivo by Engineered Lentiviral Vectors. Nature Methods. 2009. 6(1):63-6. Epub 2008 Nov 30. Featured in: News and Views: Medina & Slacks. Nature Methods 2009. Times cited:104

Brown BD, Naldini L. Exploiting and antagonizing miRNA regulation for therapeutic and experimental applications. Nature Reviews Genetics. 2009.10(8):578-85. Times cited:115

Di Stefano B*, Maffioletti SM*, Gentner B*, Ungaro F, Schira G, Naldini L, Broccoli V. A miRNA-Based System for Selecting and Maintaining the Pluripotent State in Human Induced Pluripotent Stem Cells. Stem Cells. 2011. 29(11): 1684-95. Epub 2011 Nov 1. *First Authors: BDS, SMM and BG. Co-senior authors: LN and VB. Times cited:11

Gentner B*, Visigalli I*, Hiramatsu H*, Lechman ER*, Ungari S, Giustacchini A, Schira G, Amendola M, Quattrini A, Martino S, Orlacchio A, Dick J, Biffi A, Naldini L. Identification of Hematopoietic Stem Cell-Specific miRNAs Enables Gene Therapy of Globoid Leukodystrophy. Science Translational Medicine. 2010. 2(58):58ra84. *Co-first authors: BG, IV, HH, EL. Co-senior and corresponding authors: AB and LN. Featured in: Commentary: Burgess. Nat Rev Genet. 2011 Jan;12(1):4.

Lechman ER*, Gentner B*, van Galen P*, Giustacchini A*, Saini M, Boccalatte FE, Hiramatsu H, Restuccia U, Bachi A, Voisin V, Bader GD, Dick JE, Naldini L. Attenuation of miR-126 Activity Expands HSC In Vivo without Exhaustion. Cell Stem Cell. 2012. 11(6):799-811. doi: 10.1016/j.stem.2012.09.001. Epub 2012 Nov 8. *Co-first authors ERL, BG, PvG, AG. Co-senior corresponding authors: LN and JED.

Amendola M, Giustacchini A, Gentner B, Naldini L. A Double Switch Vector System Positively Regulates Transgene Expression by Endogenous microRNA Expression (miR-ON Vector). Molecular Therapy. 2013, in press.

EXPLOITING ENGINEERED ENDONUCLEASES FOR GENE EDITING IN HUMAN STEM CELLS

Lombardo A, Genovese P, Beausejour C, Colleoni S, Lee YL, Kim KA, Ando D, Urnov F, 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. 25(11):1298-306. Epub 2007 Oct.28. Featured in: Preview: L.M Ptaszek, C.A Cowan. Cell Stem Cell 1 (6), pp. 600-602; 2007. Research Highlight L.Flintoft. Nature Reviews in Genetics. Dec 8, 908-909.Times cited:271

Lombardo A, Cesana D, Genovese P, Di Stefano B, Provasi E, Colombo D, Neri M, Magnani Z, Cantore A, Lo Riso P, Damo M, Muniz Pello O, Holmes MC, Gregory PD, Gritti A, Broccoli V, Bonini C, Naldini L. Site-specific integration and in situ tailoring of cassette design allow “sustainable” gene transfer. Nature Methods. 2011. 8(10):861-9. Featured in: Perspective: Sadelain M, Papapetrou EP, Bushman FD. Nat Rev Cancer. Dec 1;12:51-8.2011. Times cited:17

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. 29(9):816-23. Co-first authors: RG and AL. Co-senior and corresponding authors: LN and CvonK. Featured in: Research Highlights: Casci T. Nature Reviews in Genetics. Aug 31;12(10):667. 2011; Community Corner: Nature Medicine. Oct 11;17(10):1192-3. 2011; News: H.Ledford. Nature News. 7 August 2011; News and Views: Mussolino C. & Cathomen T. Nature Methods. 8,725–726. 2011. Times cited:47

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 F, 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. 18(5):807-15. *Co-first authors: EP and PG. Corresponding authors: LN and CB.Featured in: Research Highlights: Kreisberg J. Nature Biotechnology 2012. 30(5):411. Times cited:7

LIVER GENE TRANSFER AND HEMOPHILIA GENE THERAPY

Follenzi A, Battaglia M, Lombardo A, Annoni A, Roncarolo MG, Naldini L. Targeting Lentiviral Vector Expression to Hepatocytes Limits Transgene-Specific Immune Response and Establishes Long-Term Expression of Human Antihemophilic Factor IX in Mice. Blood. 2004. 103(10):3700-9. Times cited:124

Brown BD, Venneri MA, Zingale A, Sergi Sergi L, Naldini L. Endogenous microRNA Regulation Suppresses Transgene Expression in Hematopoietic Lineages and Enables Stable Gene Transfer. Nature Medicine. 2006 May;12(5):585-91. Times Cited:164

Brown BD, Sitia G, Annoni A, Hauben E, Sergi Sergi L, Zingale A, Roncarolo MG, Guidotti LG, Naldini L. In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promoters vector clearance. Blood. 2007. 109(7):2797-805; Epub 2006 Dec 19. Times cited:63

Brown BD, Cantore A, Annoni A, Sergi Sergi L, Lombardo A, Della Valle P, D’Angelo A, Naldini L. A microRNA-regulated lentiviral vector mediates stable correction of Hemophilia B mice. Blood. Plenary paper. 2007. 110(13):4144-52. Epub 2007 Aug.28. Times cited:95

Annoni A*, Brown BD*, Cantore A, Sergi Sergi L, Naldini L, Roncarolo MG. In vivo Delivery of a MicroRNA Regulated Transgene Induces Antigen-specific Regulatory T Cells and Promotes Immunological Tolerance. Blood. 2009. 114(25):5152 61. *Co-first authors: AA, BDB. Senior authors: LN and MGR. Times cited:34

Mátrai J*, Cantore A*, Bartholomae CC*, Annoni A*, Wang W, Acosta-Sanchez A, Samara-Kuko E, De Waele L, Ma L, Genovese P, Damo M, Arens A, Goudy K, Nichols TC, von Kalle C, Chuah MK, Roncarolo MG, Schmidt M, Vandendriessche T, Naldini L. Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk. Hepatology. 2011. 53(5):1696-707. *Co-first authors: JM, AC, CCB, AA. Co-senior and corresponding authors: LN, TV, MS and MGR. Times cited:19

Cantore A*, Nair N*, Della Valle P, Di Matteo M, Màtrai J, Sanvito F, Brombin C, Di Serio C, D’Angelo A, Chuah M, Naldini L, Vandendriessche T. Hyperfunctional coagulation factor IX improves the efficacy of gene therapy in hemophilic mice. Blood. 2012. 120(23):4517-20. doi: 10.1182/blood-2012-05-432591. Epub 2012 Oct 4. *Co-first authors: AC, NN. Co-senior and corresponding authors: LN and TV. Featured in: Commentary: Lozier J. Blood 2012 Nov 29;120(23):4452-3.

TIE2-EXPRESSING MONOCYTES: FROM CONTRIBUTION TO ANGIOGENESIS AND TISSUE REGENERATION TO EXPLOITATION FOR TARGETING GENE THERAPY TO TUMORS

De Palma M, Venneri MA, Roca C, Naldini L. Targeting Exogenous Genes to Tumor Angiogenesis by Transplantation of Genetically modified Hematopoietic Stem Cells. Nature Medicine. 2003. 9(6):789-95. Times cited:307

De Palma M*, Venneri MA*, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 Identifies a Hematopoietic Lineage of Pro-Angogenic Monocytes Required for Tumor Vessel Formation and a Mesenchymal Population of Pericyte Progenitors. Cancer Cell. 2005. 8(3):211-26. *Co-first authors: MDP and MAV Featured in: Highlight: Nat. Rev Cancer. 2005 Nov;5(11):842. Times cited:433

Venneri MA, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, Mazzieri R, Doglioni C, Naldini L. Identification of Proangiogenic TIE2-Expressing Monocytes (TEMs) in Human Peripheral Blood and Cancer. Blood. 2007. 109(12):5276-85. Epub 2007 Feb 27. Featured in: Preview: Coukos, Blood, Jun 15;109(12):5076. Times cited:129

De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE. Tie2-expressing Monocytes: Regulation of Tumor Angiogenesis and Therapeutic Implications. Trends Immunology. 2007. 28(12):545-50. Epub 2007 Nov 5. Times cited:75

Lewis CE, De Palma M, Naldini L. Tie2-expressing Monocytes: Regulation by Hpoxia and angioprotein. Cancer Research. 2007. 67(18):8429-32. Times cited:76

De Palma M*, Mazzieri R*, Politi LS, Pucci F, Zonari E, Mazzoleni S, Sitia G, Moi D, Venneri MA, Indraccolo S, Falini A, Guidotti LG, Galli R,  Naldini L. Tumor-targeted interferon-α delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell. 2008. 14(4):299-311. *Co-first authors: MDP and RM. Corresponding authors: LN and MDP. Times cited:75

Pucci F*, Venneri MA*, Biziato D, Nonis A, Moi D, Sica A, Di Serio C, Naldini L, De Palma M. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes (TEMs), blood “resident” monocytes and embryonic macrophages suggests common functions and developmental relationships. Blood. 2009. 114(4):901-14. Epub 2009 Apr 21. *Co-first authors: FP and MAV. Co-senior and corresponding authors: LN and MDP.Featured in: Preview: Yoder: Blood, Jul 23; 114(4):756-7. Times cited: 86

Mazzieri R*, Pucci F*, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, Naldini L, De Palma M. Targeting the Angiopoietin-2/TIE2 axis Inhibits Tumor Progression and Metastasis by Impairing Angiogenesis and Disabling Rebounds of Proangiogenic Myeloid Cells. Cancer Cell. 2011. 19(4):512-26. Co-first authors: RM and FP. Co-senior and corresponding authors: LN and MDP.Featured in: Preview: Lewis & Ferrara: Cancer Cell 2011 Apr 12;19(4):431-3 Breaking advance: Cancer Research, 2011 Apr 15. Times cited:35

Escobar G, Moi D, Ranghetti A, Ozkal-Baydin P, Squadrito ML, Kajaste-Rudnitski A, Bondanza A, Gentner B, De Palma M, Mazzieri R, Naldini L. Genetic Engineering of Hematopoiesis for Targeted IFN-α Delivery Inhibits Breast Cancer Progression. Sci Transl Med. 2014 Jan 1;6(217):217ra3.

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