Sustained Correction of a Murine Model of Phenylketonuria following a Single Intravenous Administration of AAVHSC15-PAH.

Autor:	Ahmed SS; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Rubin H; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Wang M; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Faulkner D; In Vivo Group, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Sengooba A; In Vivo Group, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Dollive SN; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Avila N; In Vivo Group, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Ellsworth JL; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Lamppu D; Program Management Group, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Lobikin M; Process Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Lotterhand J; In Vivo Group, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Adamson-Small L; Process Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Wright T; Toxicology Group, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Seymour A; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA., Francone OL; Research and Development, Homology Medicines, 1 Patriots Park, Bedford, MA 01730, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Mar 13; Vol. 17, pp. 568-580. Date of Electronic Publication: 2020 Mar 13 (Print Publication: 2020).
DOI:	10.1016/j.omtm.2020.03.009
Abstrakt:	Phenylketonuria is an inborn error of metabolism caused by loss of function of the liver-expressed enzyme phenylalanine hydroxylase and is characterized by elevated systemic phenylalanine levels that are neurotoxic. Current therapies do not address the underlying genetic disease or restore the natural metabolic pathway resulting in the conversion of phenylalanine to tyrosine. A family of hepatotropic clade F adeno-associated viruses (AAVs) was isolated from human CD34 + hematopoietic stem cells (HSCs) and one (AAVHSC15) was utilized to deliver a vector to correct the phenylketonuria phenotype in Pah enu2 mice. The AAVHSC15 vector containing a codon-optimized form of the human phenylalanine hydroxylase cDNA was administered as a single intravenous dose to Pah enu2 mice maintained on a phenylalanine-containing normal chow diet. Optimization of the transgene resulted in a vector that produced a sustained reduction in serum phenylalanine and normalized tyrosine levels for the lifespan of Pah enu2 mice. Brain levels of phenylalanine and the downstream serotonin metabolite 5-hydroxyindoleacetic acid were restored. In addition, the coat color of treated mice darkened following treatment, indicating restoration of the phenylalanine metabolic pathway. Taken together, these data support the potential of an AAVHSC15-based gene therapy as an investigational therapeutic for phenylketonuria patients. (© 2020 The Author(s).)
Databáze:	MEDLINE
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