Enhancement of therapeutic transgene insertion for treatment of murine phenylketonuria.

ABSTRACT: Low in vivo transgene integration frequency limits the therapeutic efficacy of homology-directed repair (HDR) as a treatment for genetic disorders. This study demonstrates improved efficacy of HDR-mediated gene insertion for the treatment of murine phenylalanine hydroxylase (PAH) deficiency, a model of human phenylketonuria (PKU), through pharmacologic inhibition of competing DNA repair pathways. The targeted integration of a Pah-expressing transgene was enhanced with vanillin, a potent inhibitor of non-homologous end joining (NHEJ), reducing mean serum phenylalanine concentrations by 56.8% in treated mice. This was further improved following co-inhibition of NHEJ and microhomology-mediated end joining (MMEJ), yielding transgene insertions in approximately 10% of genomes with

SUBMITTER: Martinez MA 

PROVIDER: S-EPMC12818206 | biostudies-literature | 2026 Mar

REPOSITORIES: biostudies-literature