San Raffaele Telethon Institute for Gene Therapy
Gene and neural stem cell therapy for lysosomal storage diseases
Our work is focused on evaluating novel gene therapy strategies based on lentiviral-mediated gene transfer to the CNS, either as single treatment or coupled to neural and hematopoietic stem cell transplantation (to target the PNS and periphery) to treat neurodegenerative lysosomal storage disorders (LSDs), rare genetic disease casues by genetic deficiency of specific lysosomal enzymes.
A critical part of our research is devoted to clarify the early pathogenic events and the therapeutic mechanisms of disease correction upon treatments, in order to refine and implement the gene therapy strategies under testing.
Research activity
To address this issue we are exploiting several in vitro models, including patient-specific induced pluripotent stem cells (iPSCs)-based 2D and 3D cultures (organoids). We are also expanding our disease portfolio and platforms, exploring CNS-directed gene editing strategies to address currently untreatable CNS disorders of glial cells.
Ricca A, Rufo N, Ungari S, Morena F, Martino S, Kulik W, Alberizzi V, Bolino A, Bianchi F, Del Carro U, Bi A & Gritti A, Combined gene/cell therapies provide long-term and pervasive rescue of multiple pathological symptoms in a murine model of globoid cell leukodystrophy. Hum. Mol. Genet., 2015, 24(12): 3372-89.
Meneghini V, Lattanzi A, Tiradani L, Bravo G, Morena F, Sanvito F, Calabria A, Bringas J, Fisher-Perkins JM, Dufour JP, Baker KC, Doglioni C, Montini E, Bunnell BA, Bankiewicz K, Martino S, Naldini L & Gritti A, Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy. EMBO Mol. Med. 2016, 8: 489–510.
Meneghini V, Frati G, Sala D, De Cicco S, Luciani M, Cavazzin C, Paulis M, Mentzen W, Morena F, Giannelli S, Sanvito F, Villa A, Bulfone A, Broccoli V, Martino S & Gritti A, Generation of Human Induced Pluripotent Stem Cell-Derived Bona Fide Neural Stem Cells for Ex Vivo Gene Therapy of Metachromatic Leukodystrophy. Stem Cells Transl. Med., 2016, 6: 352–368.
Mazzara PG, Massimino L, Pellegatta M, Ronchi G, Ricca A, Iannielli A, Giannelli SG, Cursi M, Cancellieri C, Sessa A, Del Carro U, Quattrini A, Geuna S, Gritti A, Taveggia C & Broccoli V, Two factor-based reprogramming of rodent and human broblasts into Schwann cells. Nat. Commun. 2017, 8:14088
Frati G, Luciani M, Meneghini V, De Cicco S, Ståhlman M, Blomqvist M, Grossi S, Filocamo M, Morena F, Menegon A, Martino S & Gritti A, Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy. Cell Death Dis. 2018, 9: 698.
Ornaghi F, Sala D, Tedeschi F, Ma a MC, Bazzucchi M, Morena F, Valsecchi M, Aureli M, Martino S, Gritti A. Novel bicistronic lentiviral vectors correct β-Hexosaminidase de ciency in neural and hematopoietic stem cells and progeny: implications for in vivo and ex vivo gene therapy of GM2 gangliosidosis. Neurobiol Dis. 2019 Nov 1;134:104667.
Frati G, Luciani M, Meneghini V, De Cicco S, Ståhlman M, Blomqvist M, Grossi S, Filocamo M, Morena F, Menegon A, Martino S, Gritti A. Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy. Cell Death Dis. 2018 Jun 13;9(6):698
Mazzara PG, Massimino L, Pellegatta M, Ronchi G, Ricca A, Iannielli A, Giannelli SG, Cursi M, Cancellieri C, Sessa A, Del Carro U, Quattrini A, Geuna S, Gritti A, Taveggia C, Broccoli V. Two factor-based reprogramming of rodent and human fibroblasts into Schwann cells. Nat Commun. 2017 Feb 7;8:14088.
Meneghini V, Frati G, Sala D, De Cicco S, Luciani M, Cavazzin C, Paulis M, Mentzen W, Morena F, Giannelli S, Sanvito F, Villa A, Bulfone A, Broccoli V, Martino S, Gritti A. Generation of human induced pluripotent stem cell-derived bona fide neural stem cells for ex vivo gene therapy of metachromatic leukodystrophy. Stem Cells Trasl Med. 2017 Feb;6(2):352-368.
Meneghini V, Lattanzi A, Tiradani L, Bravo G, Morena F, Sanvito F, Calabria A, Bringas J, Fisher-Perkins JM, Dufour JP, Baker KC, Doglioni C, Montini E, Bunnell BA, Bankiewicz K, Martino S, Naldini L, Gritti A. Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy. EMBO Mol Med. 2016 May 2;8(5):489-510.
Ricca A, Rufo N, Ungari S, Morena F, Martino S, Kulik W, Alberizzi V, Bolino A, Bianchi F, Del Carro U, Biffi A, Gritti A. Combined gene/cell therapies provide long-term and pervasive rescue of multiple pathological symptoms in a murine model of globoid cell leukodystrophy. Hum Mol Genet. 2015 Jun 15;24(12):3372-89.
Lattanzi A, Salvagno C, Maderna C, Benedicenti F, Morena F, Kulik W, Naldini L, Montini E, Martino S, Gritti A. Therapeutic benefit of lentiviral-mediated neonatal intracerebral gene therapy in a mouse model of globoid cell leukodystrophy. Hum Mol Genet. 2014;23:3250-3268.
Santambrogio S, Ricca A, Maderna C, Ieraci A, Aureli A, Sonnino S, Kulik W, Aimar P, Bonfanti L, Martino S, Gritti A. The galactocerebrosidase enzyme contributes to maintain a functional neurogenic niche during early post-natal CNS development. Hum Mol Genet. 2012; Nov 1;21(21):4732-50.
Neri M, Ricca A, di Girolamo I, Alcala'-Franco B, Cavazzin C, Orlacchio A, Martino S, Naldini L, Gritti A. Neural stem cell gene therapy ameliorates pathology and function in a mouse model of globoid cell leukodystrophy. Stem Cells. 2011 Oct;29(10):1559-71.
Pluchino A*, Gritti A*, Blezer E, Amadio S, Brambilla E, Borsellino G, Cossetti C, Del Carro U, Comi G, Hart B, Vescovi A, Martino G. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Annals of Neurology 2009;66(3):343-354. (*co-authorship)
Consiglio A*, Gritti A*, Dolcetta D, Follenzi A, Bordignon C, Gage FH, Vescovi AL and Naldini L. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. PNAS 2004;101(41):14835-40. (*co-authorship)
Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003;422(6933):688-94
