Genetic deficiency of beta-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.

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis / D. Sala, F. Ornaghi, F. Morena, C. Argentati, M. Valsecchi, V. Alberizzi, R. Di Guardo, A. Bolino, M. Aureli, S. Martino, A. Gritti. - In: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT. - ISSN 2329-0501. - 25:(2022 Jun 09), pp. 170-189. [10.1016/j.omtm.2022.03.011]

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

F. Ornaghi;M. Valsecchi;M. Aureli;
2022

Abstract

Genetic deficiency of beta-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.
CNS; GM2 gangliosidosis; Sandhoff disease; bone marrow transplantation; cell therapy; gene therapy; hexosaminidase; lentiviral vectors; lysosomal storage disorders
Settore BIO/10 - Biochimica
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S2329050122000419-main_compressed.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 4.91 MB
Formato Adobe PDF
4.91 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/944965
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact