Full-length ATP7B reconstituted through protein trans-splicing corrects Wilson disease in mice.

ABSTRACT: Wilson disease (WD) is a genetic disorder of copper homeostasis, caused by deficiency of the copper transporter ATP7B. Gene therapy with recombinant adeno-associated vectors (AAV) holds promises for WD treatment. However, the full-length human ATP7B gene exceeds the limited AAV cargo capacity, hampering the applicability of AAV in this disease context. To overcome this limitation, we designed a dual AAV vector approach using split intein technology. Split inteins catalyze seamless ligation of two separate polypeptides in a highly specific manner. We selected a DnaE intein from Nostoc punctiforme (Npu) that recognizes a specific tripeptide in the human ATP7B coding sequence. We generated two AAVs expressing either the 5'-half of a codon-optimized human ATP7B cDNA

SUBMITTER: Padula A 

PROVIDER: S-EPMC9436707 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature