Provided herein are methods and compositions related to nucleic acids encoding ornithine transcarbamylase (OTC), such as nucleic acids comprising an OTC codon- optimized sequence, as well as related vectors, such as AAV vectors. Also, provided are methods for administering AAV vectors that comprise a sequence that encodes an enzyme associated with an urea cycle disorder and an expression control sequence, in combination with synthetic nanocarriers coupled to an immunosuppressant.