ArticleProceedings of the National Academy of Sciences of the United States of America2007
Existence of transient functional double-stranded DNA intermediates during recombinant AAV transduction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 97 citations in OpenAlex.
- Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.Pediatric pulmonology · 2019Trial
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- Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.Journal of cardiac failure · 2009Trial
- Targeting the peripheral nervous system in adipose tissue with engineered AAV vectors.Cell reports methods · 2026Article
- Rapid neuronal labeling and functional imaging in the developing mouse brain with AAV-PHP.eB.Cell reports methods · 2026Article
- Article
- New hope for older SMA patients with next-generation self-complementary AAV gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Review
- Enhanced Discriminability of Viral Vectors in Viscous Nanopores.Small methods · 2025Article
- Development of circular AAV cargos for targeted seamless insertion with large serine integrases.Molecular therapy. Methods & clinical development · 2025Article
- Highly efficientMolecular therapy. Methods & clinical development · 2025Article
- Review
- Prospective approaches to gene therapy computational modeling - spotlight on viral gene therapy.Journal of pharmacokinetics and pharmacodynamics · 2024Review
- Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration.Nature biotechnology · 2024Article
- Genome-wide CRISPR screenings identified SMCHD1 as a host-restricting factor for AAV transduction.PLoS pathogens · 2024Article
- A novel class of self-complementary AAV vectors with multiple advantages based on cceAAV lacking mutant ITR.Molecular therapy. Methods & clinical development · 2024Article
- Precise genome-editing in human diseases: mechanisms, strategies and applications.Signal transduction and targeted therapy · 2024Review
- Thyroid Hormone Clearance in the Paraventricular Nucleus of Male Mice Regulates Lean Mass and Physical Activity.Neuroendocrinology · 2024Article
- Article
- MiR133b-mediated inhibition of EGFR-PTK pathway promotes rAAV2 transduction by facilitating intracellular trafficking and augmenting second-strand synthesis.Journal of cellular and molecular medicine · 2023Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Previous studies have documented that 0.1 approximately 1% of input recombinant adeno-associated virus (rAAV) vectors could be stabilized and lead to transgene expression. To characterize the steps involving massive AAV DNA loss, we designed an"AAV footprinting" strategy that can track newly formed AAV dsDNA genomes. This strategy is based on an ROSA26R mouse model or cell line that carries a lacZ gene flanked by two loxP sites. When it is transduced by a rAAV vector carrying the Cre recombinase, the lacZ gene can be activated and remain active even when rAAV genomes are later lost. By using this sensitive AAV footprinting technique, we confirmed the existence of transient AAV dsDNA that went undetected by conventional DNA methods. Although these dsDNA intermediates could be efficiently formed in almost every cell and were competent for mRNA transcription and protein synthesis in vivo, they got lost continuously. Only a small fraction was eventually stabilized for sustained gene expression. Although both rAAV2 and rAAV8 can potentially have similar levels of dsDNA formation, AAV8 dsDNA was formed much faster than that of AAV2, which explains why rAAV8 is more efficient than rAAV2 in transducing the liver. Collectively, our studies suggested that rather than receptor binding, viral entry, and ssDNA to dsDNA conversion, the instability of newly formed AAV dsDNA was the primary contributing factor for the low rAAV transduction efficacy. The uncoating step significantly influenced the stability of AAV transient dsDNA. The identification of transient AAV dsDNA provided a new pathway for improving rAAV transduction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.