Gene therapy approach to FAP: in vivo influence of T119M in TTR deposition in a transgenic V30M mouse model
| Autor: | Ana Rita Batista, Miguel Sena-Esteves, Davide Gianni, Maria João Saraiva, Miguel Ventosa, Ana Varela Coelho, Maria Rosário Almeida |
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| Rok vydání: | 2014 |
| Předmět: |
Genetic Markers
Proteomics endocrine system Pathology medicine.medical_specialty Transgene Genetic enhancement Genetic Vectors Mice Transgenic Mice In vivo Peripheral Nervous System Genetics medicine Extracellular Animals Prealbumin Electrophoresis Gel Two-Dimensional Molecular Biology Regulation of gene expression Amyloid Neuropathies Familial Extracellular Matrix Proteins Gastrointestinal tract biology Endoplasmic reticulum Gene Transfer Techniques nutritional and metabolic diseases Genetic Therapy Dependovirus Endoplasmic Reticulum Stress Disease Models Animal Transthyretin Gene Expression Regulation Liver Matrix Metalloproteinase 9 biology.protein Cancer research Molecular Medicine |
| Zdroj: | Gene Therapy. 21:1041-1050 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of amyloid fibrils composed by mutated transthyretin (TTR) mainly in the peripheral nervous system. At present, liver transplantation is still the standard treatment to halt the progression of clinical symptoms in FAP, but new therapeutic strategies are emerging, including the use of TTR stabilizers. Here we propose to establish a new gene therapy approach using adeno-associated virus (AAV) vectors to deliver the trans-suppressor TTR T119M variant to the liver of transgenic TTR V30M mice at different ages. This TTR variant is known for its ability to stabilize the tetrameric protein. Analysis of the gastrointestinal tract of AAV-treated animals revealed a significant reduction in deposition of TTR non-fibrillar aggregates in as much as 34% in stomach and 30% in colon, as well as decreased levels of biomarkers associated with TTR deposition, namely the endoplasmic reticulum stress marker BiP and the extracellular matrix protein MMP-9. Moreover, we showed with different studies that our approach leads to an increase in tetrameric and more stable forms of TTR, in favor of destabilized monomers. Altogether our data suggest the possibility to use this gene therapy approach in a prophylactic manner to prevent FAP pathology. |
| Databáze: | OpenAIRE |
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