CRISPR Prime Editing of Mitochondrial Heteroplasmy in Rare Kearns-Sayre Syndrome - Ocular and Cardiac Synergies

Sep 29, 2026

Uploaded by acoobca

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disorder combining ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects. It is driven by mitochondrial DNA (mtDNA) deletions and heteroplasmic imbalance between normal and abnormal mtDNA populations. Current therapies are largely supportive and do not correct the underlying genetic cause. CRISPR Prime Editing (PE), a precise and RNA-less approach, may directly correct pathogenic mtDNA variants by restoring the wild-type to variant ratio, improving ocular and cardiac disease manifestations. Tissue-specific delivery (e.g., AAV2 vectors or cardiomyocyte promoters) could enhance targeting and facilitate translation to clinical care.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages2

Reading Time5 min

AccessFree to download

Abstract

Ethical approval

Consent

Sources of funding

Author contributions

Conflicts of interest disclosure

Letter to the Editor CRISPR prime editing of mitochondrialheteroplasmyin rare Kearns-Sayre syndrome: # ocular and cardiac synergies Sarim Hassan Shahab, MBBSa , Fazal Habib, MBBSb ,* Abstract 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) deletionsand heteroplasmic imbal -ance, where there is a variation in levels of normal versus abnormal mtDNA. Current therapies offer symptomatic relief at most; theydo not address the primary issue of correcting the genetic mutation. Innovative methods employing CRISPR Prime Editing (PE), anaccurate and RNA-less technology, allow for unique correction of pathogenic mtDNA variants and errors. By fixing the wild type tovariant ratio, PE could directly correct ocular- and cardiac-related signs and symptoms inKSS, in two tissue types that are entirelydependent on mitochondrial bioenergetics for their energy needs. Furthermore, the use of tissue-specific delivery methods, suchas AAV2 vectors or cardiomyocyte promoters, would further enhance the targeting of the corrective approach to more specificallycorrect disease processes. This represents a completely innovative approach to genomic correction in the field of mitochondrialmedicine, and thereis important to translate this research to the clinic. Kearns-Sayre syndrome (KSS) remains a rare, but severe form ofmitochondrial cytopathy with ophthalmoplegia, pigmentaryretinopathy, and conduction disease [1] . Despite advances inmolecular diagnostics, subsequent therapeutic interventionsremain largely supportive. The development of CRISPR depen -dent mitochondrial editing systems, and CRISPR Prime Editing(PE) in particular, represents a paradigm shift toward true man -agement of mitochondrial diseases caused by mtDNAheteroplasmy[2] . Recent developments have addressed the singular and tediousaspects of injecting the mitochondrial genome – such as fixingthe requirement for guide RNAs and non-specific off-targetcleavage – using RNA-free base editors and mitochondrialnickases[3] . In the case ofKSS, where the oxidative phosphoryla -tion mechanism is affected by pathological large-scale deletionsin mtDNA, PE of the mitochondrial genome can preciselyremove heteroplasmic imbalances to reinstate the relative wild -type genome within the mtDNA population[4] . This PE could aDepartment of Internal Medicine, Nishtar Medical University, Multan, Pakistan andbDepartment of Internal Medicine, Sher-e-Bangla Medical College, Barisal,Bangladesh Sponsorships or competing interests that maybe relevant to content are disclosedatthe end of this article. *Corresponding author. Address: Department of Internal Medicine, Sher-e-BanglaMedical College, Barisal 8200, Bangladesh. E-mail: fazalhabib346@gmail.com (F.Habib). Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This is anopen access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non -commercial, as long as itis passed along unchanged and in whole, with credit to theauthor. Annals of Medicine & Surgery (2026) 88:1019–1020Received 4 November 2025; Accepted 6 November 2025Published online 14 November 2025http://dx.doi.org/10.1097/MS9.0000000000004366 alleviate some of the ocular and cardiomyopathy complicationsassociated with KSS, as these tissues are particularly dependenton mitochondria to fuel their respective energy needs. The com -parison between conventional and CRISPR-based interventionsin KSS highlights the unique advantages of precision mitochon -drial correction over symptomatic care (Table 1) . Additionally, ocular gene delivery systems (e.g., AAV2 vec -tors) combined with cardiomyocyte-specific promoters providea collaborative avenue for tissue-specific repair that may limitsystemic exposure[5] . While the need for precli

FAQs

What causes Kearns-Sayre syndrome at the mitochondrial DNA level?

KSS arises from mtDNA deletions and heteroplasmic imbalance, meaning levels of normal versus abnormal mtDNA vary within tissues.

How does CRISPR Prime Editing (PE) aim to treat KSS differently from current therapies?

PE targets pathogenic mtDNA by enabling precise correction to restore the wild-type to variant ratio, addressing the genetic origin rather than only providing symptomatic support.

Why are ocular and cardiac tissues highlighted as key targets for PE in KSS?

The document emphasizes that these tissues rely heavily on mitochondrial bioenergetics for their energy needs, so correcting mitochondrial heteroplasmy may alleviate related signs and symptoms.

Sep 29, 2026

Uploaded by acoobca