CRISPR prime editing of mitochondrial heteroplasmy in rare Kearns-Sayre syndrome: ocular and cardiac synergies.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disorder defined by a combination of ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects. KSS arises from mitochondrial DNA (mtDNA) deletions and heteroplasmic imbalance, where there is a variation in levels of normal versus abnormal mtDNA. Current therapies offer symptomatic relief at most; they do not address the primary issue of correcting the genetic mutation. Innovative methods employing CRISPR Prime Editing (PE), an accurate and RNA-less technology, allow for unique correction of pathogenic mtDNA variants and errors. By fixing the wild type to variant ratio, PE could directly correct ocular- and cardiac-related signs and symptoms in KSS, in two tissue types that are entirely dependent on mitochondrial bioenergetics for their energy needs. Furthermore, the use of tissue-specific delivery methods, such as AAV2 vectors or cardiomyocyte promoters, would further enhance the targeting of the corrective approach to more specifically correct disease processes. This represents a completely innovative approach to genomic correction in the field of mitochondrial medicine, and there is important to translate this research to the clinic.