ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
AAV vector-derived elements integrate into Cas9-generated double-strand breaks and disrupt gene transcription.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Functional editing of the OTC locus by targeted integration with phenotype correction and restoration of endogenous expression patterns.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- On-target and off-target activities of CRISPR therapeutics across scales.Trends in biotechnology · 2026Review
- UBE3A isoform-selective and non-selective contributions to Angelman syndrome phenotypes.Molecular psychiatry · 2026Article
- Nickase NmCas9 unsilences paternal Ube3a in a mouse model of Angelman syndrome without causing AAV vector integration.Scientific reports · 2026Article
- Gene therapy for liver diseases: methods, challenges and opportunities.Journal of nanobiotechnology · 2026Review
- CRISPR-Cas9 Therapeutics in Early Clinical Development: Delivery and Molecular Diagnostics.Cells · 2026Review
- Review
- Advancements in CRISPR-basedFrontiers in genome editing · 2026Review
- Multi-targeting zinc finger nuclease vector unsilences paternal UBE3A in a mouse model of Angelman syndrome.Gene therapy · 2026Article
- Compact Calm1 promoter enables AAV mediated neuron-targeted expression in human iPSC-derived brain organoids.Scientific reports · 2025Article
- UBE3A stabilization of β-catenin preserves synaptic proteins essential for motor and cognitive functions in Angelman Syndrome.Molecular autism · 2025Article
- AAV-dCas9 vector unsilences paternal Ube3a in neurons by impeding Ube3a-ATS transcription.Communications biology · 2025Article
- Recent advances in therapeutic gene-editing technologies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- A human Angelman Syndrome class II pluripotent stem cell line with fluorescent paternalFrontiers in cell and developmental biology · 2025Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
We previously developed an adeno-associated virus (AAV) Cas9 gene therapy for Angelman syndrome that integrated into the genome and prematurely terminated Ube3a-ATS. Here, we assessed the performance of 3 additional AAV vectors containing S. aureus Cas9 in vitro and in vivo, and 25 vectors containing N. meningitidis Cas9 in vitro, all targeting single sites within Ube3a-ATS. We found that none of these single-target gRNA vectors were as effective as multi-target gRNA vectors at reducing Ube3a-ATS expression in neurons. We also developed an anchored multiplex PCR sequencing method and analysis pipeline to quantify the relative frequency of all possible editing events at target sites, including AAV integration and unresolved double-strand breaks. We found that integration of AAV was the most frequent editing event (67%-89% of all edits) at three different single target sites, surpassing insertions and deletions (indels). None of the most frequently observed indels were capable of blocking transcription when incorporated into a Ube3a-ATS minigene reporter, whereas two vector derived elements-the poly(A) and reverse promoter-reduced downstream transcription by up to 50%. Our findings suggest that the probability that a gene trapping AAV integration event occurs is influenced by which vector-derived element(s) are integrated and by the number of target sites.
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What Socratic holds
Registered trials
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 Socratic graph.