An Overview of Nonclinical and Clinical Liver Toxicity Associated With AAV Gene Therapy

This article reviews the presentation given at the 2023 annual meeting of the Society of Toxicologic Pathology (STP) on liver toxicity observed with adeno-associated viral vector (AAV) gene therapy. After decades as a therapeutic modality largely confined to the academic research environment, gene therapy has emerged in recent years as a rapidly expanding therapeutic approach in the biopharmaceutical industry with AAV as the most commonly used viral vector for gene delivery. This interest in the field of gene therapy by industry has been enhanced by the recent success of approved therapies for curing genetic diseases such as ZOLGENSMA for spinal muscular atrophy and LUXTURNA for Leber congenital amaurosis. However, recently reported clinical and nonclinical toxicities highlight the challenges in safely developing AAV gene therapies that require high dose systemic administration. The presentation reviewed general attributes of AAV as a gene therapy vector, clinical and nonclinical liver toxicity associated with AAV gene therapy and the potential for a multimodal immune suppression strategy that may mitigate toxicities.

Automated summary

This article reviews the presentation at the 2023 STP annual meeting on liver toxicity observed with AAV gene therapy. Gene therapy has gained popularity in recent years, particularly using AAV as the viral vector. However, reported toxicities in clinical and nonclinical settings pose challenges for the development of AAV gene therapies that require high systemic doses. The presentation discussed the characteristics of AAV as a gene therapy vector, liver toxicity associated with AAV gene therapy, and potential immune suppression strategies to mitigate toxicity.