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

Autor:	Wang L; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Warzecha CC; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Kistner A; Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA 94949, USA., Chichester JA; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Bell P; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Buza EL; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., He Z; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Pampena MB; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Couthouis J; Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA 94949, USA., Sethi S; Charles River Laboratories Inc., Reno, NV 89511, USA., McKeever K; Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA 94949, USA., Betts MR; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Kakkis E; Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA 94949, USA., Wilson JM; Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Wadsworth S; Ultragenyx Gene Therapy, Ultragenyx Pharmaceutical Inc., Cambridge, MA 02139, USA., Sullivan BA; Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA 94949, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2022 Jan 19; Vol. 24, pp. 292-305. Date of Electronic Publication: 2022 Jan 19 (Print Publication: 2022).
DOI:	10.1016/j.omtm.2022.01.007
Abstrakt:	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. Competing Interests: A.K., J.C., K.M., S.W., E.K., and B.A.S. are employees of Ultragenyx Pharmaceutical Inc. J.M.W. is a paid advisor to and holds equity in Scout Bio and Passage Bio; he also has sponsored research agreements with Amicus Therapeutics, Biogen, Elaaj Bio, FA212, Janssen, Passage Bio, and Scout Bio, which are licensees of Penn technology. He also has a sponsored research agreement with G2 Bio. J.M.W. holds equity in the G2-Bio-associated asset companies. J.M.W. and L.W. are inventors on patents that have been licensed to various biopharmaceutical companies and for which they may receive payments. (© 2022 The Authors.)
Databáze:	MEDLINE
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