Correction of homoplasmic mitochondrial tRNA mutation in patient-derived iPSCs via DdCBE

Primary mitochondrial diseases (PMD) are a group of rare, heterogeneous disorders with mitochondrial defects, which are often caused by pathogenic mutations in mitochondrial associating genes. Currently, effective treatments are still lacking clinically validation, and urgently needed in clinic. Homoplasmic m.A4300G has been documented as a pathogenic mtDNA mutation leading to maternally inherited hypertrophic cardiomyopathy (HCM) and defected function of mitochondrial respiratory chain in cardiac tissue. In this study, we achieved efficient correction of m.A4300G in iPSCs, with few off-target editing, and recovered the mitochondrial functions correspondingly. Our proof of principle work provided evidence that homoplasmic pathogenic mtDNA mutation can be genetically corrected, together with the restoring of the mitochondrial functions.