Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector
Giulia De Sabbata, Florence Boisgérault, Corrado Guarnaccia, Alessandra Iaconcig, Giulia Bortolussi, Fanny Collaud, Giuseppe Ronzitti, Marcelo Simon Sola, Patrice Vidal, Jérémy Rouillon, Séverine Charles, Emanuele Nicastro, Lorenzo D’Antiga, Petr O. Ilyinskii, Federico Mingozzi, Takashi Kishimoto, Andrés F. Muro
Abstract
mice (5.0E11 vg/kg) mediated long-term complete correction of the phenotype. Adeno-Associated viral (AAV) vector treatment restored the physiological ammonia detoxification liver function, as indicated by urinary orotic acid normalization and by conferring full protection against an ammonia challenge. Removal of liver-specific transcription factor binding sites from the AAV backbone did not affect gene expression levels, with a potential improvement in safety. These results demonstrate that AAV8-hOTC-CO gene transfer is safe and results in sustained correction of OTCD in mice, supporting the translation of this approach to the clinic.