Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis
Genetic deficiency of β-N-acetylhexosaminidase (Hex) functionality leads to accumulation of GM2 ganglioside in Tay-Sachs disease and Sandhoff disease (SD), which presently lack approved therapies. Current experimental gene therapy (GT) approaches with adeno-associated viral vectors (AAVs) still pose...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122000419 |
| _version_ | 1819022808192122880 |
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| author | Davide Sala Francesca Ornaghi Francesco Morena Chiara Argentati Manuela Valsecchi Valeria Alberizzi Roberta Di Guardo Alessandra Bolino Massimo Aureli Sabata Martino Angela Gritti |
| author_facet | Davide Sala Francesca Ornaghi Francesco Morena Chiara Argentati Manuela Valsecchi Valeria Alberizzi Roberta Di Guardo Alessandra Bolino Massimo Aureli Sabata Martino Angela Gritti |
| author_sort | Davide Sala |
| collection | DOAJ |
| description | Genetic deficiency of β-N-acetylhexosaminidase (Hex) functionality leads to accumulation of GM2 ganglioside in Tay-Sachs disease and Sandhoff disease (SD), which presently lack approved therapies. Current experimental gene therapy (GT) approaches with adeno-associated viral vectors (AAVs) still pose safety and efficacy issues, supporting the search for alternative therapeutic strategies. Here we leveraged the lentiviral vector (LV)-mediated intracerebral (IC) GT platform to deliver Hex genes to the CNS and combined this strategy with bone marrow transplantation (BMT) to provide a timely, pervasive, and long-lasting source of the Hex enzyme in the CNS and periphery of SD mice. Combined therapy outperformed individual treatments in terms of lifespan extension and normalization of the neuroinflammatory/neurodegenerative phenotypes of SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in brain tissues that single treatments failed to achieve. Our results highlight the synergic mode of action of LV-mediated IC GT and BMT, clarify the contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of corrective enzymatic activity. These results have important implications for interpretation of ongoing experimental therapies and for design of more effective treatment strategies for GM2 gangliosidosis. |
| first_indexed | 2024-12-21T04:28:53Z |
| format | Article |
| id | doaj.art-61bdd9f6fc0d43f78a06d041a2b5f2f0 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-21T04:28:53Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-61bdd9f6fc0d43f78a06d041a2b5f2f02022-12-21T19:15:59ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-06-0125170189Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosisDavide Sala0Francesca Ornaghi1Francesco Morena2Chiara Argentati3Manuela Valsecchi4Valeria Alberizzi5Roberta Di Guardo6Alessandra Bolino7Massimo Aureli8Sabata Martino9Angela Gritti10San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, ItalyDepartment of Chemistry, Biology, and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, ItalyDepartment of Chemistry, Biology, and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20090 Segrate, MI, ItalyDivision of Neuroscience, San Raffaele Scientific Institute, INSPE, Via Olgettina 58, 20132 Milan, ItalyDivision of Neuroscience, San Raffaele Scientific Institute, INSPE, Via Olgettina 58, 20132 Milan, ItalyDivision of Neuroscience, San Raffaele Scientific Institute, INSPE, Via Olgettina 58, 20132 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20090 Segrate, MI, ItalyDepartment of Chemistry, Biology, and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy; Corresponding author Angela Gritti, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.Genetic deficiency of β-N-acetylhexosaminidase (Hex) functionality leads to accumulation of GM2 ganglioside in Tay-Sachs disease and Sandhoff disease (SD), which presently lack approved therapies. Current experimental gene therapy (GT) approaches with adeno-associated viral vectors (AAVs) still pose safety and efficacy issues, supporting the search for alternative therapeutic strategies. Here we leveraged the lentiviral vector (LV)-mediated intracerebral (IC) GT platform to deliver Hex genes to the CNS and combined this strategy with bone marrow transplantation (BMT) to provide a timely, pervasive, and long-lasting source of the Hex enzyme in the CNS and periphery of SD mice. Combined therapy outperformed individual treatments in terms of lifespan extension and normalization of the neuroinflammatory/neurodegenerative phenotypes of SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in brain tissues that single treatments failed to achieve. Our results highlight the synergic mode of action of LV-mediated IC GT and BMT, clarify the contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of corrective enzymatic activity. These results have important implications for interpretation of ongoing experimental therapies and for design of more effective treatment strategies for GM2 gangliosidosis.http://www.sciencedirect.com/science/article/pii/S2329050122000419lysosomal storage disordersGM2 gangliosidosisgene therapyCNSbone marrow transplantationlentiviral vectors |
| spellingShingle | Davide Sala Francesca Ornaghi Francesco Morena Chiara Argentati Manuela Valsecchi Valeria Alberizzi Roberta Di Guardo Alessandra Bolino Massimo Aureli Sabata Martino Angela Gritti Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis Molecular Therapy: Methods & Clinical Development lysosomal storage disorders GM2 gangliosidosis gene therapy CNS bone marrow transplantation lentiviral vectors |
| title | Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis |
| title_full | Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis |
| title_fullStr | Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis |
| title_full_unstemmed | Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis |
| title_short | Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis |
| title_sort | therapeutic advantages of combined gene cell therapy strategies in a murine model of gm2 gangliosidosis |
| topic | lysosomal storage disorders GM2 gangliosidosis gene therapy CNS bone marrow transplantation lentiviral vectors |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122000419 |
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