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Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression
Lili Wang1, Claude C Warzecha1, Alexander Kistner2
1Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
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.
Insights
Gene therapy with DTX301 shows promise for ornithine transcarbamylase deficiency. This study found no significant differences between sexes or the impact of immunosuppression on treatment outcomes in macaques.
Area of Science:
- Genetics
- Gene Therapy
- Biochemistry
Background:
- Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked genetic urea cycle disorder.
- It causes hyperammonemia, neurological issues, and can be fatal.
- DTX301, a gene therapy using scAAV8, is a potential treatment for OTCD, but its efficacy concerning sex and immunosuppression is unclear.
Purpose of the Study:
- To investigate the impact of sex and prophylactic immunosuppression on DTX301 gene therapy outcomes in adult cynomolgus macaques.
- To assess the safety and tolerability of DTX301 in male and female macaques, with and without immunosuppression.
Main Methods:
- Four groups of adult cynomolgus macaques (n=3/group) were studied: male non-immunosuppressed, male immunosuppressed, female non-immunosuppressed, and female immunosuppressed.
- DTX301 was administered, and outcomes were monitored up to day 140.
- Analyses included vector genome and transgene expression, and hepatic interferon gene signature.
Main Results:
- DTX301 was well tolerated in all groups, with no significant differences observed between sexes or immunosuppression status.
- A trend towards increased vector genome and transgene expression was noted in prednisolone-treated animals, but not statistically significant.
- Prednisolone treatment significantly decreased the hepatic interferon gene signature, showing an inverse relationship with vector DNA and transgene RNA, though this effect diminished upon withdrawal of immunosuppression.
Conclusions:
- DTX301 gene therapy is well-tolerated and shows similar outcomes in male and female macaques, regardless of immunosuppression.
- Prophylactic immunosuppression with prednisolone may enhance gene expression and reduce interferon response, but further studies are needed to determine the long-term effects and optimal use.
- These findings contribute to understanding the variables influencing gene therapy efficacy in OTCD.
