Novel 5′ untranslated region (UTR)-targeting gene knock-in (KI) compositions and methods of use are disclosed. The gene KI compositions and methods exploit homology-independent targeted integration (HITI)-mediated insertion of a wild-type coding sequence (CDS) into the 5′ UTR upstream of a translation initiation element of a mutated variant of the wild-type gene. The 5′ UTR-targeting gene KI therapy compositions and methods provide safer and more efficient gene insertion compared to other gene therapy approaches.