Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease.
Mol Ther
; 32(6): 1701-1720, 2024 Jun 05.
Article
en En
| MEDLINE
| ID: mdl-38549375
ABSTRACT
Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter-AAV9-gfaABC(1)D-EIF2B5-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Terapia Genética
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Astrocitos
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Dependovirus
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Factor 2B Eucariótico de Iniciación
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Modelos Animales de Enfermedad
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Leucoencefalopatías
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Vectores Genéticos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos