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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