Ability of adeno-associated virus serotype 8-mediated hepatic expression of acid alpha-glucosidase to correct the biochemical and motor function deficits of presymptomatic and symptomatic Pompe mice.
Hum Gene Ther
; 19(6): 609-21, 2008 Jun.
Article
em En
| MEDLINE
| ID: mdl-18500944
ABSTRACT
The availability of a murine model of Pompe disease has enabled an evaluation of the relative merits of various therapeutic paradigms, including gene therapy. We report here that administration of a recombinant adeno-associated virus serotype 8 (AAV8) vector (AAV8/DC190-GAA) encoding human acid alpha-glucosidase (GAA) into presymptomatic Pompe mice resulted in nearly complete correction of the lysosomal storage of glycogen in all the affected muscles. A relatively high dose of AAV8/DC190-GAA was necessary to attain a threshold level of GAA for inducing immunotolerance to the expressed enzyme and for correction of muscle function, coordination, and strength. Administration of AAV8/DC190-GAA into older Pompe mice with overt disease manifestations was also effective at correcting the lysosomal storage abnormality. However, these older mice exhibited only marginal improvements in motor function and no improvement in muscle strength. Examination of histologic sections showed evidence of skeletal muscle degeneration and fibrosis in aged Pompe mice whose symptoms were abated or rescued by early but not late treatment with AAV8/DC190-GAA. These results suggest that AAV8-mediated hepatic expression of GAA was effective at addressing the biochemical and functional deficits in Pompe mice. However, early therapeutic intervention is required to maintain significant muscle function and should be an important consideration in the management and treatment of Pompe disease.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Doença de Depósito de Glicogênio Tipo II
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Dependovirus
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Alfa-Glucosidases
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Vetores Genéticos
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Fígado
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Hum Gene Ther
Assunto da revista:
GENETICA MEDICA
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TERAPEUTICA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos