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Adeno-Associated Viral Vector Serotype 5 Poorly Transduces Liver in Rat Models
- Source :
- PLoS ONE, PLoS ONE, Vol 8, Iss 12, p e82597 (2013), PLoS ONE, 8(12). Public Library of Science, PLoS ONE; Vol 8
- Publication Year :
- 2013
- Publisher :
- Public Library of Science (PLoS), 2013.
-
Abstract
- Preclinical studies in mice and non-human primates showed that AAV serotype 5 provides efficient liver transduction and as such seems a promising vector for liver directed gene therapy. An advantage of AAV5 compared to serotype 8 already shown to provide efficient correction in a phase 1 trial in patients suffering from hemophilia B, is its lower seroprevalence in the general population. Our goal is liver directed gene therapy for Crigler-Najjar syndrome type I, inherited severe unconjugated hyperbilirubinemia caused by UGT1A1 deficiency. In a relevant animal model, the Gunn rat, we compared the efficacy of AAV 5 and 8 to that of AAV1 previously shown to be effective. Ferrying a construct driving hepatocyte specific expression of UGT1A1, both AAV8 and AAV1 provided an efficient correction of hyperbilirubinemia. In contrast to these two and to other animal models AAV5 failed to provide any correction. To clarify whether this unexpected finding was due to the rat model used or due to a problem with AAV5, the efficacy of this serotype was compared in a mouse and two additional rat strains. Administration of an AAV5 vector expressing luciferase under the control of a liver specific promoter confirmed that this serotype poorly performed in rat liver, rendering it not suitable for proof of concept studies in this species.
- Subjects :
- Serotype
Glucuronosyltransferase
Clinical Research Design
Genetic enhancement
Population
lcsh:Medicine
Gastroenterology and Hepatology
Viral vector
03 medical and health sciences
Transduction (genetics)
Model Organisms
0302 clinical medicine
Genomic Medicine
Genetics
medicine
Animal Models of Disease
Liver Disease and Pregnancy
lcsh:Science
education
Biology
030304 developmental biology
Clinical Genetics
0303 health sciences
education.field_of_study
Multidisciplinary
biology
Liver Diseases
lcsh:R
Human Genetics
Gene Therapy
Genomics
Animal Models
Gunn rat
Virology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Hepatocyte
Immunology
biology.protein
Medicine
lcsh:Q
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e382aa88f6078b27ea60e84df7e27a88