Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis.
CNS
GM2 gangliosidosis
Sandhoff disease
bone marrow transplantation
cell therapy
gene therapy
hexosaminidase
lentiviral vectors
lysosomal storage disorders
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
09 Jun 2022
09 Jun 2022
Historique:
received:
27
12
2021
accepted:
13
03
2022
entrez:
18
4
2022
pubmed:
19
4
2022
medline:
19
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35434178
doi: 10.1016/j.omtm.2022.03.011
pii: S2329-0501(22)00041-9
pmc: PMC8983315
doi:
Types de publication
Journal Article
Langues
eng
Pagination
170-189Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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