Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper-dependent adenoviral vectors

Background: Helper-dependent adenoviral vectors (HDAd) can mediate long-term phenotypic correction in the ornithine transacarbamylase (OTC)-deficient mice model with negligible chronic toxicity. However, the high doses required for metabolic correction will result in systemic inflammatory response syndrome in humans. This acute toxicity represents the major obstacle for clinical applications of HDAd vectors for the treatment of OTC deficiency. Strategies for reducing the dose necessary for disease correction are highly desirable because HDAd acute toxicity is clearly dose-dependent. Methods: We analysed a potent expression cassette and the hydrodynamic injection for the ability to reduce the HDAd dose necessary for phenotypic correction in OTC-deficient spf-ash mice. Results: We have developed a vector containing a potent expression cassette expressing the OTC transgene, which allowed phenotypic correction at lower doses. Our results suggest that vector expressing greater OTC levels allows correction of orotic acid overproduction at lower doses that make clinical translation more relevant. We were able to further reduce the minimal effective dose by delivering the vector through the hydrodynamic injection technique. Conclusions: Vectors containing the expression cassette used in the present study, combined with other strategies for improving HDAd therapeutic index, will likely permit application of these vectors for the treatment of OTC deficiency as well as other urea cycle disorders.