Base Editing of the Recessive POLG A467T/A449T Mutation for the Treatment of POLG-Related Disorders

Mitochondrial diseases are a heterogeneous group of genetic disorders caused by mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA), often resulting in impaired oxidative phosphorylation and reduced cellular energy production. Among nuclear-encoded genes essential for mitochondrial function, the polymerase gamma gene (POLG) plays a critical role in mitochondrial DNA replication and repair. Mutations in POLG are associated with a spectrum of mitochondrial disorders, with the recessive A467T/A449T mutation representing one of the most common and clinically significant variants. Currently, therapeutic options for POLG-related diseases remain limited and are largely supportive, highlighting the need for targeted molecular approaches. Base editing, a CRISPR-derived genome editing technology, enables precise nucleotide conversions without inducing double-strand DNA breaks, offering a promising strategy for correcting pathogenic point mutations. This thesis explores the potential of base editing as a therapeutic approach for the correction of the recessive POLG A467T/A449T mutation. The molecular basis of POLG-related disease, the principles of base editing technology, and the feasibility of applying this approach to POLG mutations are examined. Key challenges, including targeting efficiency, off-target effects, and delivery constraints, are discussed.