Disclosed herein are codon-optimized nucleic acids encoding a reduced-size ATP7A protein. Also disclosed are vectors and recombinant viruses (such as recombinant adeno-associated viruses) including the codon-optimized nucleic acids encoding the reduced-size ATP7A protein and compositions including the disclosed vectors and viruses. Further disclosed herein are methods of treating copper transport disorders, for example by administering a disclosed nucleic acid, vector, or recombinant virus to a subject with a copper transport disorder, such as Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.

The present disclosure provides compositions and methods for gene therapy. Further, the present disclosure provides compositions and methods for treatment of Wilson's Disease through novel gene therapy mechanisms. Wherein a composition of a closed circular cDNA integrating gene therapy construct, the gene therapy construct comprising, from 5 to 3, a polynucleotide sequence is disclosed.