Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression

• Published in: Molecular therapy. Methods & clinical development 2022-03, Vol.24, p.292-305
• Main Authors: Wang, Lili, Warzecha, Claude C., Kistner, Alexander, Chichester, Jessica A., Bell, Peter, Buza, Elizabeth L., He, Zhenning, Pampena, M. Betina, Couthouis, Julien, Sethi, Sunjay, McKeever, Kathleen, Betts, Michael R., Kakkis, Emil, Wilson, James M., Wadsworth, Samuel, Sullivan, Barbara A.
• Format: Article
• Language: English
• Subjects: AAV8; adeno-associated virus; IFN gene signature; immunosuppression; liver; non-human primates; Original; ornithine transcarbamylase deficiency; sex
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2022.01.007

Ornithine transcarbamylase deficiency is a rare X-linked genetic urea cycle disorder leading to episodes of acute hyperammonemia, adverse cognitive and neurological effects, hospitalizations, and in some cases death. DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency; however, the impact of sex and prophylactic immunosuppression on ornithine transcarbamylase gene therapy outcomes is not well characterized. This study sought to describe the impact of sex and immunosuppression in adult, sexually mature female and male cynomolgus macaques through day 140 after DTX301 administration. Four study groups (n = 3/group) were included: male non-immunosuppressed; male immunosuppressed; female non-immunosuppressed; and female immunosuppressed. DTX301 was well tolerated with and without immunosuppression; no notable differences were observed between female and male groups across outcome measures. Prednisolone-treated animals exhibited a trend toward greater vector genome and transgene expression, although the differences were not statistically significant. The hepatic interferon gene signature was significantly decreased in prednisolone-treated animals, and a significant inverse relationship was observed between interferon gene signature levels and hepatic vector DNA and transgene RNA. These observations were not sustained upon immunosuppression withdrawal. Further studies may determine whether the observed effect can be prolonged. [Display omitted] DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency. In nonhuman primates, Wang et al. demonstrate that DTX301 outcomes were not affected by sex. Moreover, prophylactic immunosuppression in this model led to transient increased transgene expression and decreased interferon gene signature.