Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.
Mol Ther
; 26(3): 874-889, 2018 03 07.
Article
em En
| MEDLINE
| ID: mdl-29433937
ABSTRACT
We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function. Bone marrow transplantation, performed in this protocol without immunosuppressive preconditioning, added minimal benefits to the AAV9 gene therapy. Contrasting with other proposed pre-clinical therapies, these results demonstrate that achieving nearly complete correction of GALC's metabolic deficiencies across the entire nervous system via gene therapy can have a significant improvement to behavioral deficits, pathophysiological changes, and survival. These results are an important consideration for determining the safest and most effective manner for adapting gene therapy to treat this leukodystrophy in the clinic.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Terapia Genética
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Metabolismo dos Carboidratos
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Galactosilceramidase
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Leucodistrofia de Células Globoides
Tipo de estudo:
Diagnostic_studies
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Guideline
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Ther
Assunto da revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos