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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Sep 01, 2015 |
| Title |
Genotoxicity after adeno-associated virus (AAV) gene therapy is dependent upon dose, treatment age and enhancer-promoter selection (microRNA) |
| Platform organism |
synthetic construct |
| Sample organism |
Mus musculus |
| Experiment type |
Non-coding RNA profiling by array
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| Summary |
AAV gene therapy has recently been approved for clinical use and shown to be efficacious and safe in a growing number of clinical trials. However, the safety of AAV as a gene therapy has been challenged by a few studies that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. The association between AAV and HCC has been difficult to reconcile and is the subject of intense debate because numerous AAV studies have not reported toxicity. Here, we report a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the Rian locus and the over-expression of a proximal gene, Rtl1, were associated with HCC. In addition, we identify a number of genes with differential expression that maybe useful in the study, diagnosis and treatment of HCC. We demonstrate that AAV vector dose, enhancer-promoter selection, and the timing of gene delivery are the defining factors in AAV-mediated insertional mutagenesis. Our results help explain the AAV-mediated genotoxicity previously observed and have important implications for the design of both safer AAV vectors and gene therapy studies.
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| Overall design |
To investigate the possibility that insertional mutagenesis by AAV contributed to the development of HCC, we collected normal and tumor tissues from adult mouse livers that received AAV injection at a neonatal stage.
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| Contributor(s) |
Chandler RJ, Elkahloun AG, Venditti CP, Wu W |
| Citation(s) |
25607839 |
| Submission date |
Sep 22, 2014 |
| Last update date |
Jan 22, 2020 |
| Contact name |
abdel G Elkahloun |
| E-mail(s) |
abdel@mail.nih.gov
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| Phone |
301 402 3170
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| Organization name |
NHGRI-NIH
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| Lab |
MICROARRAY CORE
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| Street address |
50, SOUTH DRIVE
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| City |
BETHESDA |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL16384 |
[miRNA-3] Affymetrix Multispecies miRNA-3 Array |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA261716 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE61632_RAW.tar |
44.2 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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