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Changing trends in the development of AAV-based gene therapies: a meta-analysis of past and present therapies

Gene Therapy volume 30, pages 323–335 (2023)Cite this article

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Abstract

Gene therapy has seen a transformation from a proof-of-concept approach to a clinical reality over the past several decades, with adeno-associated virus (AAV)-mediated gene therapy emerging as the leading platform for in vivo gene transfer. A systematic review of AAV-based gene therapies in clinical development was conducted herein to determine why only a handful of AAV-based gene therapy products have achieved market approval. The indication to be treated, route of administration and vector design were investigated as critical factors and assessed for their impact on clinical safety and efficacy. A shift in recent years towards high-dose systemic administration for the treatment of metabolic, neurological and haematological diseases was identified, with intravenous administration demonstrating the highest efficacy and safety risks in clinical trials. Recent years have seen a decline in favour of traditional AAV serotypes and promoters, accompanied by an increase in favour and higher clinical success rate for novel capsids and tissue-specific promoters. Furthermore, a meta-analysis was performed to identify factors that may inhibit the translation of therapeutic efficacy from preclinical large animal studies to first-in-human clinical trials and a detrimental effect on clinical efficacy was associated with alterations to administration routes.

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Fig. 1: PRISMA 2020 flow diagram displaying the identification and screening process of study selection and the quantity and types of records included in the analysis.
Fig. 2: AAV-based gene therapy by therapeutic area (n = 217).
Fig. 3: Efficacy and safety of AAV-based gene therapy by therapeutic area.
Fig. 4: AAV-based gene therapy by route of administration.
Fig. 5: Efficacy and safety of AAV-based gene therapy by route of administration.
Fig. 6: AAV-based gene therapy by vector design.
Fig. 7: Efficacy and safety of AAV-based gene therapy by AAV serotypes.
Fig. 8: Efficacy and safety of AAV-based gene therapy by AAV promoters.
Fig. 9: The effect of changing route of administration from preclinical studies to clinical trials.
Fig. 10: The effect of fold change in dose from preclinical studies to clinical trials.

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Data availability

Data generated and analysed within this study can be found within the supplementary files associated with the submission.

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Acknowledgements

I thank Clinton Greggor for his encouragement and support throughout the writing of this article.

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    Tamara Burdett & Samir Nuseibeh

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TB was responsible for conducting all data collection/extraction and analysis, interpretation of results and writing. SN acted as project supervisor and provided the initial concept and framework in addition to thorough feedback/assistance in data collection, analysis and writing of the report.

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Burdett, T., Nuseibeh, S. Changing trends in the development of AAV-based gene therapies: a meta-analysis of past and present therapies. Gene Ther 30, 323–335 (2023). https://doi.org/10.1038/s41434-022-00363-0

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