ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Increasing the Specificity of AAV-Based Gene Editing through Self-Targeting and Short-Promoter Strategies.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.Science translational medicine · 2026Article
- Review
- Phospholipase C epsilon 1 as a therapeutic target in cardiovascular diseases.Journal of advanced research · 2025Review
- Engineering adeno-associated viral vectors for CRISPR/Cas based in vivo therapeutic genome editing.Biomaterials · 2025Review
- Exploring AAV-Mediated Gene Therapy for Inner Ear Diseases: from Preclinical Success to Clinical Potential.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Gene editing therapy as a therapeutic approach for cardiovascular diseases in animal models: A scoping review.PloS one · 2025Article
- Therapeutic Gene Editing in Dyslipidemias.Reviews in cardiovascular medicine · 2024Review
- Gene Editing for the Treatment of Hypercholesterolemia.Current atherosclerosis reports · 2024Review
- Applications of Genome Editing Technologies in CAD Research and Therapy with a Focus on Atherosclerosis.International journal of molecular sciences · 2023Review
- Vector Affinity and Receptor Distribution Define Tissue-Specific Targeting in an Engineered AAV Capsid.Journal of virology · 2023Article
- Gene editing for dyslipidemias: New tools to "cut" lipids.Atherosclerosis · 2023Review
- Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases.Human gene therapy · 2022Article
- PCSK9 Monoclonal Antibodies: New Developments and Their Relevance in a Nucleic Acid-Based Therapy Era.Current atherosclerosis reports · 2022Review
- Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics.Science advances · 2022Article
- AAV-mediated gene therapy: Advancing cardiovascular disease treatment.Frontiers in cardiovascular medicine · 2022Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Our group previously used adeno-associated viral vectors (AAVs) to express an engineered meganuclease specific for a sequence in the PCSK9 gene (M2PCSK9), a clinical target for treating coronary heart disease. Upon testing this nuclease in non-human primates, we observed specific editing characterized by several insertions and deletions (indels) in the target sequence as well as indels in similar genomic sequences. We hypothesized that high nuclease expression increases off-target editing. Here, we reduced nuclease expression using two strategies. The first was a self-targeting strategy that involved inserting the M2PCSK9 target sequence into the AAV genome that expresses the nuclease and/or fusing the nuclease to a specific peptide to promote its degradation. The second strategy used a shortened version of the parental promoter to reduce nuclease expression. Mice administered with these second-generation AAV vectors showed reduced PCSK9 expression due to the nuclease on-target activity and reduced off-target activity. All vectors induced a stable reduction of PCSK9 in primates treated with self-targeting and short-promoter AAVs. Compared to the meganuclease-expressing parental AAV vector, we observed a significant reduction in off-target activity. In conclusion, we increased the in vivo nuclease specificity using a clinically relevant strategy that can be applied to other genome-editing nucleases.
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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 OpenQuestion graph.