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Liver-directed gene therapy for ornithine aminotransferase deficiency.
Boffa, Iolanda; Polishchuk, Elena; De Stefano, Lucia; Dell'Aquila, Fabio; Nusco, Edoardo; Marrocco, Elena; Audano, Matteo; Pedretti, Silvia; Caterino, Marianna; Bellezza, Ilaria; Ruoppolo, Margherita; Mitro, Nico; Cellini, Barbara; Auricchio, Alberto; Brunetti-Pierri, Nicola.
Afiliación
  • Boffa I; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • Polishchuk E; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • De Stefano L; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • Dell'Aquila F; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • Nusco E; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • Marrocco E; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • Audano M; Department of Pharmacology and Biomolecular Sciences, University of Milan, Milan, Italy.
  • Pedretti S; Department of Pharmacology and Biomolecular Sciences, University of Milan, Milan, Italy.
  • Caterino M; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
  • Bellezza I; CEINGE - Biotecnologie Avanzate s.c.a.r.l., Naples, Italy.
  • Ruoppolo M; Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, Perugia, Italy.
  • Mitro N; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
  • Cellini B; CEINGE - Biotecnologie Avanzate s.c.a.r.l., Naples, Italy.
  • Auricchio A; Department of Pharmacology and Biomolecular Sciences, University of Milan, Milan, Italy.
  • Brunetti-Pierri N; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
EMBO Mol Med ; 15(4): e17033, 2023 04 11.
Article en En | MEDLINE | ID: mdl-36647689
Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno-associated (AAV8) vector expressing OAT under the control of a hepatocyte-specific promoter. Following injections, OAT-deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV-injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one-year post-injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof-of-concept of efficacy of liver-directed AAV-mediated gene therapy of GACR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Atrofia Girata Límite: Animals Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Atrofia Girata Límite: Animals Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido