We thank Dr. Jesse Riordan for his letter in response to our recently published review article in Human Gene Therapy entitled “AAV Infection: Protection from Cancer,”
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as well as for pointing out that the human MEG8 gene is the ortholog of the Rian locus in the mouse. However, the fact remains that integrations in the Rian locus leading to hepatocellular carcinoma (HCC) have thus far been documented only in mice. No integration of either the wild-type (WT) or the recombinant AAV (rAAV) genomes into the MEG8 locus has been reported to date in humans. Thus, the prediction that “it is reasonable to assume that integrations within the MEG8 locus will occur at some rate in treated patients” is purely conjectural and must await the test of time. Furthermore, as we have stated previously,
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it is important to emphasize that up to 90% of the human population is seropositive for AAV2,
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and this stands in stark contrast to an HCC prevalence of fewer than 10 cases of HCC per 100,000 in the United States, a rate that appears to be increasing coincident with the prevalence of hepatitis C virus infection.
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It is difficult to explain this if AAV infection truly represents a significant risk for HCC development.
The argument that “targeted integration of rAAV integration at the Rian locus identified strong resemblance to a specific subclass of human HCC associated with poor prognosis” is still limited to the mouse model. It may well be that “valuable insights may be gained from mouse models of HCC caused by Rian integrations.” However, we maintain that, generally speaking, rodent models are poor surrogates for humans. A cogent example is the absence of an immune response to rAAV vectors in mouse models of hemophilia B, whereas in clinical trials in patients with hemophilia B performed with various rAAV serotype vectors, an immune response to AAV capsid proteins has been observed.
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In summary, we concur with Schmidt et al.,
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who continue to challenge the suggestion that the WT AAV plays an oncogenic role, as well as with Kay and Nakai,
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who have concluded that the risk of cancer induced by rAAV vectors is negligible.
