Two Extensive Studies Conducted in Non-Human Primates Suggests Minimal Cancer Risk in Human Gene Therapy Using Adeno-Associated Viruses

New research conducted by the University of Pennsylvania’s Gene Therapy Program (GTP) suggests that adeno-associated viruses (AAVs), which can be genetically modified to deliver DNA to specific cells, are unlikely to cause cancer-inducing insertions in humans or monkeys. Furthermore, this research indicates that AAVs may contribute to the long-term effectiveness of gene therapy.

In gene therapy, AAVs are frequently utilized as carriers to deliver therapeutic genes into target cells. One potential concern with this approach is that these AAVs can sometimes become integrated into the chromosomal DNA of the host, leading to worries that such insertions could disrupt the host genome, potentially causing cellular dysfunction or cancer development.¹

Previous studies in mice, especially in newborn mice, indicated that these insertions could potentially trigger liver cancer by disrupting critical regulatory elements within the genome. Whether this risk translates to humans and other primates remained uncertain.

However, two extensive studies conducted in non-human primates have shed light on this issue. These studies reveal that vector integrations in primate liver, following AAV gene therapy, might be a crucial mechanism for achieving sustained gene expression. Importantly, these integrations are unlikely to induce cancer-causing mutations in humans. These findings align with the low-risk integration patterns observed in natural, non-pathogenic AAV infections.

In one of the studies published in Human Gene Therapy², researchers at the University of Pennsylvania analyzed tissue samples, primarily from the livers of 86 macaque monkeys treated with AAV-based gene therapies during preclinical trials. Additionally, they examined 253 macaques and humans who had never been exposed to engineered AAVs.

The results indicated that the engineered AAVs in the gene therapy recipients, as well as the naturally occurring (“wild-type”) AAVs in the control group, were integrated into the genome at low rates and distributed randomly across the genome. Importantly, the risk of expansion was low, even in a monkey studied 15 years after treatment.

In the other study published in Nature Biotechnology³, researchers followed 12 macaques for over 2 years after they received AAV-based gene therapies targeting liver cells. They discovered complex structures of AAV genomes outside the chromosome, which persisted but appeared to be rapidly inactivated soon after vector delivery. Integrated forms of vector DNA were observed at lower frequencies, consistent with the number of cells that stably expressed the transgene. This suggests that the durability of AAV gene therapy in primate livers may be attributed to integrated forms of the vector.

Once again, the researchers found a low frequency of AAV vector sequences embedded in chromosomal DNA, distributed across various sites within the genomes. Importantly, none of these integration sites were in close proximity to genes whose disruption has been linked to liver cancer, and there was no evidence of significant clonal expansion during the years of follow-up.
James M. Wilson, MD, Ph.D., the senior author of the study and director of the Gene Therapy Program at the University of Pennsylvania, commented on the findings, stating, “These studies provide insights into new strategies for improving liver gene therapy, emphasizing the importance of gene expression rather than just delivery. Our data also underscore the potential benefits of genome editing for the liver, where insertions can be directed to safe regions of the chromosome, in contrast to the more widespread integrations that occur with the vector alone.”

These promising findings regarding the safety of AAV-based gene therapy in non-human primate (NHP) studies highlight the potential benefits of gene delivery and genome editing for therapeutic purposes. However, maintaining strict control and monitoring of AAV quality for NHP studies can be challenging for researchers. Fortunately, PackGene can provide valuable assistance in this regard. We offer specialized AAV packaging services tailored specifically for NHP studies. Our NHP-grade AAV undergoes rigorous quality control, ensuring high titers and efficient administration with minimal toxicity in primates and large animals. This not only streamlines research efforts but also reduces safety risks to animals, representing a crucial step in bridging the gap between preclinical studies and future clinical applications.

Reference:

1. Integration of Gene Therapy Vectors: A Risk Factor for Tumorigenesis or Another Commensal Property of Adeno-Associated Viruses That Benefits Long-Term Transgene Expression? Phillip W.L. Tai Hum Gene Ther. (2023) https://doi.org/10.1089/hum.2023.29255.pwl

2. Prevalent and Disseminated Recombinant and Wild-Type Adeno-Associated Virus Integration in Macaques and Humans. Martins K. M. et al. Hum Gene Ther. (2023) https://doi.org/10.1089/hum.2023.134

3. Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration. Greig, J.A., Martins, K.M., Breton, C. et al. Nat Biotechnol (2023). https://doi.org/10.1038/s41587-023-01974-7

4. AAV-based gene therapies in non-human primates suggest integration into human DNA is unlikely to drive cancer mutations. https://medicalxpress.com/news/2023-11-aav-based-gene-therapies-non-human-primates.html

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