Assessment of emerin gene transfer in models of X-linked Emery-Dreifuss muscular dystrophy

X-linked Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin, a 254-amino acid integral protein of the inner nuclear membrane. Given that almost all EMD mutations lead to loss of protein expression, we hypothesized that emerin replacement gene therapy could be an effective strategy to treat X-linked EDMD. We designed a serotype rh74 adeno-associated virus vector containing a tMCK promoter linked to a codon-optimized human emerin cDNA (AAV-tMCK-hEMD) to drive emerin expression in striated muscle. We administered this vector to Emd −/y mice and examined emerin expression and assessed various safety parameters. We also examined emerin expression in EMD −/y induced pluripotent stem cell-derived cardiomyocytes. Treatment with AAV-tMCK-hEMD produced robust expression of human emerin in heart and skeletal muscle of Emd −/y mice as demonstrated by immunoblotting and immunofluorescence microscopy. Systemic administration of AAV-tMCK-hEMD to Emd −/y mice did not lead to significant alterations in serum biochemistries, heart, skeletal muscle or liver histology, or major gene expression changes in the heart. Transduction of EMD −/y induced pluripotent stem cell-derived cardiomyocytes with AAV-tMCK-hEMD resulted in emerin expression, demonstrating its utility in a human striated muscle cell model system. These results showing effective adeno-associated virus vector-mediated expression of emerin in striated muscle in preclinical models provide proof of concept for potential emerin gene therapy in patients with X-linked EDMD.