A mitochondrial disease model is generated and corrected using engineered base editors in rat zygotes

Area of Science:

• Genetics
• Molecular Biology
• Biotechnology

Background:

• Mitochondrial DNA (mtDNA) mutation generation and correction present significant challenges.
• Leigh syndrome is a severe genetic disorder often linked to mtDNA defects.

Purpose of the Study:

• To develop efficient methods for generating and correcting mtDNA mutations in vivo.
• To create reliable rat models for studying Leigh syndrome and testing therapeutic interventions.

Main Methods:

• Embryonic injection of an engineered mtDNA adenine base editor (eTd-mtABE) to induce mutations.
• Development and subsequent injection of a precise mtDNA C-to-T base editor into mutated embryos for correction.

Main Results:

• Successfully generated Leigh syndrome rat models with high efficiency (up to 74%) in the F0 generation.
• Achieved an average restoration of 53% wild-type mtDNA alleles after base editor treatment.
• Observed amelioration of disease symptoms in the corrected rat models.

Conclusions:

• The study demonstrates the feasibility of efficient mtDNA mutation generation and correction using base editors in vivo.
• Engineered base editors offer a promising therapeutic strategy for genetic disorders caused by mtDNA mutations.
• This work provides valuable tools and models for advancing mitochondrial disease research.