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Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver
Open accessAbstract
Vectors based on adeno-associated virus (AAV) are effective in gene delivery in vivo. Tissue-specific gene expression is often needed to minimize ectopic expression in unintended cells and undesirable consequences. Here, we investigated whether incorporation of target sequences of tissue-specific microRNA (miRNA) into AAV vectors could inhibit ectopic expression in tissues such as the liver and hematopoietic cells. First we inserted liver-specific miR-122 target sequences (miR-122T) into the 3'-untranslated region (UTR) of a number of AAV vectors. After intravenous delivery in mice, we found that five copies of the 20mer miR-122T reduced liver expression of luciferase by 50-fold and β-galactosidase (LacZ) by 70-fold. Five copies of miR-122T also reduced mRNA levels of a secretable protein (myostatin propeptide) from the AAV vector plasmid by 23-fold in the liver. However, gene expression in other tissues, including the heart was not inhibited. Similarly, we inserted four copies of miR-142-3pT or miR-142-5pT, both hematopoietic lineage-specific, into the 3'-UTR of the AAV-luciferase vector. We wished to see whether they could prolong transgene expression by inhibiting expression in antigen-presenting cells. However, in vivo luciferase gene expression in major tissues declined with time, regardless of the miR-142 target sequences used. Quantitative analysis of the vector DNA in various tissues revealed that the decline of transgene expression in vivo was mainly because of promoter shut-off other than loss of AAV-transduced cells by immune destruction. Moreover, transgene expression was not detected in circulating mononuclear cells after delivering AAV9 vector with or without miR142T. These results demonstrate that liver-specific miR-122 target sequence in AAV vectors was highly efficient in reducing liver expression, whereas hematopoietic miR-142 target sequences were ineffective in preventing decline of AAV vector gene expression in nonhematopoietic tissues resulted from promoter shut-off.
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“Incorporation of 5 copies of miR-122 target sequences has shown enhanced inhibitory effects over 3 copies in the liver of ICR mice, while without any significant change in transduction efficiency in 293 T cells [33].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [33]
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Metadata
- Authors
- Qiao, C., Yuan, Z., Li, J., He, B., Zheng, H., Mayer, C., Li, J., & Xiao, X.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Qiao, C
- Xiao, X
- ORCID
- He, B
- Venue
- Gene Therapy
- Published
- 2010-12-09
- Volume
- 18
- Issue
- 4
- Pages
- 403-410
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC3686499
- OpenAlex
- W2086500311
- Cited by
- 163
- References
- 62
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 16 · 2023: 10 · 2022: 7 · 2021: 13 · 2020: 8 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 6 · 2015: 12 · 2014: 11 · 2013: 11 · 2012: 8
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR45967, R01AR045967, AR 56394, R01AR056394)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus vectors, miR-122, miR-142, 3' untranslated region, liver-specific gene expression, tissue-specific gene expression, ectopic expression, hematopoietic cells, AAV9, myostatin propeptide, intravenous gene delivery
- MeSH terms
- Dependovirus, Animals, Antigen-Presenting Cells, beta-Galactosidase, Gene Expression Regulation, Genetic Vectors, Liver, Luciferases, Organ Specificity, Gene Transfer Techniques, Transgenes, MicroRNAs, Mice, Myostatin
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