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Molecular Therapy - Methods & Clinical Development
Wang, L;Warzecha, C;Kistner, A;Chichester, J;Bell, P;Buza, E;He, Z;Pampena, M;Couthouis, J;Sethi, S;McKeever, K;Betts, M;Kakkis, E;Wilson, J;Wadsworth, S;Sullivan, B;
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 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; 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 observed effect can be prolonged.