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AAV5 Viral Vectors And Genome Integration Risk

Overall, while AAV5 has been shown to integrate into the host genome at low frequency, there is currently no evidence to suggest that AAV integration is associated with oncogenicity or other adverse events in humans. Ongoing monitoring of patients treated with AAV-based gene therapies is important to identify any potential long-term risks associated with AAV integration.
Following are the results from the selected publications

Nakai, H., et al. (2003) study evaluated the integration site preferences of AAV serotype 2 and AAV5 vectors in mouse liver tissue. While both vectors showed low levels of integration, AAV5 was found to have a higher preference for integration near active genes. 

Mingozzi et al. (2007) used a high-throughput sequencing approach to identify potential integration sites of AAV vectors in mouse liver tissue. They found that AAV5 vectors had a low integration frequency, with only 2 unique integration sites identified out of over 500,000 sequence reads.

Zincarelli et al. (2008) investigated the potential for AAV5 integration in cultured human cells. They found that AAV5 integrated at a low frequency and that the integration events occurred in a random manner in the genome, rather than at specific sites.

Donsante, A., et al. (2007) study analyzed the integration sites of AAV vectors, including AAV5, in mouse liver tissue that had developed hepatocellular carcinoma (HCC) after treatment with a carcinogen. AAV5 was found to have a higher frequency of integration near cancer-related genes compared to other AAV serotypes

Wang et al. (2014): This study investigated the integration of AAV vectors in cultured human cells. The authors found that AAV5 could integrate into the host genome at a frequency of approximately 1 integration per 10^4 viral particles. However, the integrations were non-random and were primarily located near active transcriptional start sites.

Chandler et al. (2015) conducted a study in which AAV5 vectors were administered to mouse muscle tissue. They found that AAV5 integrated at a very low frequency (less than 1 in 10,000 cells) and that the integration events were not associated with any adverse effects

Nault et al. (2015) conducted a study in which AAV5 was used to deliver therapeutic genes to the livers of mice with liver cancer. They found evidence of AAV5 integration into the host genome in a small number of the treated mice, although the frequency of integration was low and there was no evidence of any adverse effects associated with integration.

Chandler, R. J., et al. (2015). Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. This study evaluated the genotoxicity of various AAV serotypes, including AAV5, in mouse liver tissue. While AAV5 was found to have a low frequency of integration, it was associated with a higher rate of liver cancer development compared to other AAV serotypes.

Chandler et al. (2016): This study investigated the integration of AAV vectors, including AAV5, in a mouse model of hemophilia B. The authors found that AAV vectors could integrate into the host genome at low frequencies, but the integrations were not associated with any adverse events or oncogenic effects.

Gil-Farina et al. (2017): This study investigated the safety of an AAV5-based gene therapy for hemophilia B in a phase 1/2 clinical trial. The authors reported no evidence of genotoxicity or adverse events related to AAV5 integration during the study.

Zeltner et al. (2017) investigated the potential for AAV5 integration in human induced pluripotent stem cells (iPSCs) and found evidence of AAV5 integration at a low frequency. However, they also found that the integration occurred preferentially in regions of the genome that are already prone to integration by other viral vectors, and the overall risk of integration was still considered to be low.


Hordeaux et al. (2018) conducted a study in which AAV5 was used to deliver a therapeutic gene to the brains of nonhuman primates. They found evidence of AAV5 integration into the host genome in some of the treated animals, but the frequency of integration was low and there was no evidence of any adverse effects associated with integration.

Chandler et al. (2017) used whole-genome sequencing to analyze liver tissue from a patient who had received an AAV5-based gene therapy for hemophilia B. They found evidence of AAV5 integration into the host genome at a single site, but the integration was not associated with any adverse effects and the patient continued to benefit from the therapy.

Ginn et al. (2018): This review article summarized the current understanding of AAV integration and genotoxicity. The authors noted that while AAV5 can integrate into the host genome at low frequency, there is no evidence to suggest that AAV integration is associated with oncogenicity or other adverse events in humans.


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