Gene therapy using Aß variants for amyloid reduction.
Mol Ther
; 29(7): 2294-2307, 2021 07 07.
Article
en En
| MEDLINE
| ID: mdl-33647457
Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid ß (Aß) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Aß variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Aß in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aß oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Aß levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aß variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Terapia Genética
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Péptidos beta-Amiloides
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Placa Amiloide
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Enfermedad de Alzheimer
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Vectores Genéticos
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos