ArticleScientific reports2023
AAV production in stable packaging cells requires expression of adenovirus 22/33K protein to allow episomal amplification of integrated rep/cap genes.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed, 11 citations in OpenAlex.
- An engineered helper plasmid generates differential E4orf6 and L4-22/33K gene expression increasing AAV vector production.Gene therapy · 2026Article
- Comparative Analysis of rAAV Production from Plasmid-Encoded Versus Chromosomally Integrated rAAV Transgene in HEK293 Cells.International journal of molecular sciences · 2026Article
- Comparative Analysis of HEK293 Genomic Variability.Biotechnology and bioengineering · 2026Article
- Exploring AAV-Mediated Gene Therapy for Inner Ear Diseases: from Preclinical Success to Clinical Potential.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Self-silencing adenovirus enables precise infectious titration of recombinant adeno-associated viral vectors.Molecular therapy. Methods & clinical development · 2025Article
- E2A, VA RNA I, and L4-22k adenoviral helper genes are sufficient for AAV production in HEK293 cells.Molecular therapy. Methods & clinical development · 2024Article
- Characterization of the function of Adenovirus L4 gene products and their impact on AAV vector production.Molecular therapy. Methods & clinical development · 2024Article
- Development of Stable Packaging and Producer Cell Lines for the Production of AAV Vectors.Microorganisms · 2024Review
- An improved high-resolution method for quantitative separation of empty and filled AAV8 capsids by strong anion exchange HPLC.Frontiers in bioengineering and biotechnology · 2024Article
- Status and future of recombinant adeno-associated virus vector manufacturing.Biotechnology progressReview
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Efficient manufacture of recombinant adeno-associated virus (rAAV) vectors for gene therapy remains challenging. Packaging cell lines containing stable integration of the AAV rep/cap genes have been explored, however rAAV production needs to be induced using wild-type adenoviruses to promote episomal amplification of the integrated rep/cap genes by mobilizing a cis-acting replication element (CARE). The adenovirus proteins responsible are not fully defined, and using adenovirus during rAAV manufacture leads to contamination of the rAAV preparation. 'TESSA' is a helper adenovirus with a self-repressing Major Late Promoter (MLP). Its helper functions enable efficient rAAV manufacture when the rep and cap genes are provided in trans but is unable to support rAAV production from stable packaging cells. Using rAAV-packaging cell line HeLaRC32, we show that expression of the adenovirus L4 22/33K unit is essential for rep/cap amplification but the proteins are titrated away by binding to replicating adenovirus genomes. siRNA-knockdown of the adenovirus DNA polymerase or the use of a thermosensitive TESSA mutant decreased adenovirus genome replication whilst maintaining MLP repression, thereby recovering rep/cap amplification and efficient rAAV manufacture. Our findings have direct implications for engineering more efficient adenovirus helpers and superior rAAV packaging/producer cells.
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