San Raffaele Telethon Institute for Gene Therapy
Gene and neural stem cell therapy for lysosomal storage diseases
Leukodystrophies (metachromatic leukodystrophy, MLD; globoid cell leukodystrophy, GLD) and GM2 gangliosidosis belong to the wider class of Lysosomal Storage Diseases (LSDs), in which deficiency of specific lysosomal enzymes results in storage of undegraded macromolecules in lysosomes, functional impairment, and cell death. Many of them display severe involvement of the central nervous system and consequent neurodegeneration.
Previous and current studies of this Unit aim to study mechanisms of disease pathogenesis and develop novel gene therapy (GT) approaches for these LSDs that despite the shared multi-organ pathology display unique features, likely translating in different treatment requirements and/or different outcome of a given treatment.
Research activity
Based on promising pre-clinical and clinical data showing the therapeutic potential of GT in LSDs, it is expected that combinatorial strategies addressing the complex LSD pathology and ensuring appropriate timing of intervention at different disease sites would become of increasing interest in the perspective of clinical translation. The long-term goal is to enhance and complement the unique treatment modality provided by GT (i.e. the advantages of enzyme overexpression and widespread biodistribution) to develop innovative and safer therapeutic strategies addressing the specific requirements posed by severe LSD that still lack effective curative options.
To this end, a better understanding of the pathogenic events underlying disease onset/progression and of the therapeutic mechanisms of disease correction upon treatments is required. To address this issue we are exploiting several in vitro experimental settings, including neural stem cell cultures as well as patient-specific induced pluripotent stem cells (iPSCs), which will offer an unprecedented opportunity to model the disease and to test novel gene transfer strategies.
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
