ArticleMolecular therapy. Methods & clinical development2025
pH-dependent DNA degradation pathways for adeno-associated virus gene therapy.
Article in Molecular therapy. Methods & clinical development, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- DNA ejection and AAV capsid degradation under thermal stress: Insights from CDMS and native digestion strategies.Molecular therapy. Advances · 2026Article
- Comprehensive forced degradation study revealing diverse chemical and physical degradation pathways of AAV8.Gene therapy · 2026Article
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Authors and funding
8 authors.
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Abstract
Adeno-associated virus (AAV) vector genome degradation mechanisms that reduce transduction efficiency and viral potency must be understood to define critical quality attributes to ensure safety and efficacy. Here, we report that under prolonged storage at 25°C with two capsid types from clade C and E and varying buffer conditions the observation of degradation of rAAV DNA. Studies revealed two main degradation mechanisms: chemical degradation of encapsidated DNA at acidic pH and ejection of DNA at basic pH, with both occurring at neutral pH. Moreover, storage of clade E capsid in acidic pH at 25°C for 7 days showed >50% potency loss, which strongly correlated with a drop in encapsidated single-stranded DNA (ssDNA) (>40%) but not with conventional attributes used to characterize AAV stability, such as vector genome titer or full percentage. Degradation of the encapsidated ssDNA could be potentially driven by low pH non-enzymatic depurination reactions, facilitated by the local DNA-protein interactions within the capsid. Therefore, DNA integrity is a product attribute that should be studied and controlled in the development of AAV-based gene therapies.
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Registered trials
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