Adeno-associated viral vector integration: implications for long-term efficacy and safety

Area of Science:

• Genetics
• Virology
• Molecular Biology

Background:

• Adeno-associated virus (AAV) vector gene therapy is a promising treatment for monogenic inherited disorders.
• Clinical trials for hemophilia show long-term expression and reduced bleeding, but unknowns remain regarding AAV vector persistence and cellular mechanisms.
• AAV is known to persist as extrachromosomal DNA (episomes) and through integration into the host cell genome.

Purpose of the Study:

• To review the current understanding of wild-type AAV (WT-AAV) and recombinant AAV (rAAV) natural history.
• To focus on the mechanisms and implications of genomic integration for AAV vectors.
• To address safety concerns related to AAV vector integration.

Main Methods:

• Literature review of studies on AAV natural history, persistence, and integration.
• Analysis of preclinical and clinical data regarding rAAV integration events.
• Examination of potential cellular mechanisms mediating AAV persistence and integration.

Main Results:

• AAV vectors primarily persist as episomes, but integration into the host genome also occurs.
• WT-AAV infection is widespread, with recent links to acute hepatitis and hepatocellular carcinoma in some cases.
• Integration of rAAV vectors has been reported in preclinical and clinical studies, with variable implications for long-term safety and efficacy.

Conclusions:

• Understanding AAV genomic integration is crucial for assessing long-term efficacy and safety of gene therapies.
• Further research is needed to clarify the consequences of AAV integration and ensure patient safety.
• This review synthesizes current knowledge on AAV natural history and genomic integration.