Related Experiment Video
Updated: Aug 15, 2025
Author Spotlight: Assessing Intrathecal Gene Therapy Efficacy in Juvenile Rats
Published on: March 29, 2024
Adeno-associated virus (AAV)-based gene therapy products: What are toxicity studies in non-human primates showing us?
Paul Baldrick1, Brian McIntosh2, Mayuri Prasad2
1Product Development and Market Access Consulting, Clinical Development & Commercialisation Services, Labcorp Drug Development Inc. (formerly Covance), Harrogate, North Yorkshire, HG3 1PY, United Kingdom.
Abstract:
A number of adeno-associated virus (AAV)-based gene therapy products have entered clinical development, with a few also reaching marketing approval. However, as our knowledge of them grows from nonclinical and clinical testing, it has become apparent that various actual and theoretical safety issues can arise from their use. This review of 19 Good Laboratory Practice (GLP)-compliant toxicity studies in non-human primates (NHPs) with AAV-based gene therapy products via a variety of different dose routes in the period 2017-2021 showed results ranging from no study findings different from controls, or findings considered to be non-adverse, to actual toxicity, with changes highlighting careful monitoring in the clinic. Similar findings were found from a review of a number of published toxicity studies in NHPs. It was confirmed that studies have a role in evaluating for dorsal root ganglion (DRG) and/or peripheral nerve toxicity, hepatotoxicity, adverse immunogenicity and, to a lesser degree, insertional mutagenesis as well as other potential unacceptable findings such as adverse inflammation for ocular therapy candidates. Overall, it was demonstrated that toxicity (and biodistribution) studies in NHPs are a vital part of the safety assessment of AAV-based gene therapy products prior to clinical entry.
Insights
Adeno-associated virus (AAV) gene therapies require careful safety evaluation. Toxicity studies in non-human primates (NHPs) are crucial for identifying potential risks before clinical use.
Area of Science:
- Gene therapy
- Toxicology
- Non-human primate models
Background:
- Adeno-associated virus (AAV)-based gene therapies are advancing into clinical trials and market approval.
- Growing knowledge highlights potential safety concerns associated with AAV gene therapy use.
Approach:
- Review of 19 Good Laboratory Practice (GLP)-compliant toxicity studies in non-human primates (NHPs) involving AAV-based gene therapy products (2017-2021).
- Analysis of published NHP toxicity studies to corroborate findings.
- Evaluation of specific toxicity endpoints including dorsal root ganglion (DRG) and peripheral nerve toxicity, hepatotoxicity, immunogenicity, insertional mutagenesis, and inflammation for ocular therapies.
Key Points:
- Toxicity study results in NHPs varied from no adverse findings to significant toxicities requiring clinical monitoring.
- Studies confirmed the importance of evaluating DRG/peripheral nerve toxicity, hepatotoxicity, and immunogenicity.
- Potential risks like insertional mutagenesis and adverse inflammation (especially for ocular therapies) were also assessed.
Conclusions:
- Non-human primate (NHP) toxicity and biodistribution studies are essential for the safety assessment of AAV-based gene therapies.
- These studies provide critical data for guiding clinical development and ensuring patient safety.
- Findings underscore the need for comprehensive safety evaluations prior to clinical application of AAV gene therapies.
