Development challenges associated with rAAV-based gene therapies

The number of gene therapies in development continues to increase. as they represent a novel method to treat, and potentially cure, many diseases. Gene therapies can be conducted with an in vivo or ex vivo approach, to cause gene augmentation, gene suppression, or genomic editing. Adeno-associated viruses are commonly used to deliver gene therapies, but their use is associated with several manufacturing, nonclinical and clinical challenges. As these challenges emerge, regulatory agency expectations continue to evolve. Following administration of rAAV-based gene therapies, nonclinical toxicities may occur, which includes immunogenicity, hepatotoxicity, neurotoxicity, and the potential risks for insertional mutagenesis and subsequent tumorgenicity. The mechanism for these findings and translation into the clinical setting are unclear at this time but have influenced the nonclinical studies that regulatory agencies are increasingly requesting to support clinical trials and marketing authorizations. These evolving regulatory expectations and toxicities, as well as future nonclinical considerations, are discussed herein.

Automated summary

Gene therapies are a novel method to potentially cure many diseases, with gene suppression or editing possible. Adeno-associated viruses are commonly used to deliver these therapies but come with manufacturing and clinical challenges. Regulatory expectations are evolving, with nonclinical toxicities such as immunogenicity and neurotoxicity being observed, influencing the regulatory studies required for clinical trials and marketing authorizations.