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Updated: Jun 1, 2026
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Transgene Expression in Cultured Cells Using Unpurified Recombinant Adeno-Associated Viral Vectors
Published on: October 20, 2023
Adeno-Associated Virus Gene Therapy: Is There a Risk of Insertional Mutagenesis?
Paul Batty1,2
1University College London, London, UK.
Toxicologic Pathology
|May 31, 2026
Summary
Recombinant adeno-associated virus (rAAV) gene therapy shows long-term safety. While wild-type AAV can integrate into the genome, rAAV primarily persists as episomes, with minimal integration risks observed in studies.
Area of Science:
- * Gene Therapy
- * Virology
- * Molecular Biology
Background:
- * Adeno-associated virus (AAV) gene therapy is approved for rare genetic disorders.
- * Understanding the natural history of recombinant AAV (rAAV) is crucial for assessing long-term safety and durability.
- * Wild-type AAV (wtAAV) can integrate into the host genome, with rare associations with cancer.
Purpose of the Study:
- * To investigate the persistence and integration patterns of recombinant AAV (rAAV) vectors.
- * To evaluate the potential risks of insertional mutagenesis associated with rAAV gene therapy.
- * To compare the behavior of rAAV with wild-type AAV (wtAAV) in biological systems.
Main Methods:
- * Review of existing literature on AAV natural history and gene therapy studies.
- * Analysis of data from murine models, large animal studies, and human biopsy samples.
- * Comparative assessment of wtAAV and rAAV structures and their biological implications.
Main Results:
- * Recombinant AAV (rAAV) primarily exists as extrachromosomal episomes, similar to wtAAV.
- * A small proportion of rAAV can integrate into the host genome.
- * Insertional mutagenesis linked to rAAV was observed in some early murine studies, particularly with high-dose or neonatal administration.
- * These mutagenic events have not been consistently reported and were absent in large animal models and human samples.
Conclusions:
- * The risk of insertional mutagenesis from rAAV gene therapy appears minimal and context-dependent.
- * Current evidence suggests rAAV gene therapy is associated with favorable long-term safety profiles.
- * Further research into rAAV natural history supports its therapeutic potential for monogenic disorders.
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