Prime Editing in Selected Disease Applications: Cancer Models, Primary Immunodeficiency, β-Hemoglobinopathies, HIV/CCR5, and Neurodegenerative Targets

Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 transformed genome engineering by enabling targeted DNA cleavage, but double-strand breaks can generate heterogeneous repair products and larger genomic alterations. Prime editing is a search-and-replace genome-editing strategy that combines a Cas9 nickase, reverse transcriptase, and prime-editing guide RNA to install defined substitutions, small insertions, and small deletions without a donor DNA template or programmed double-strand break. This narrative review evaluates selected disease applications in which prime editing has been studied directly or proposed on a strong biological rationale, with emphasis on cancer modeling and KRAS correction, patient-derived immunodeficiency models, β-hemoglobinopathies, human immunodeficiency virus (HIV)/CCR5 editing, and neurodegenerative targets. Evidence is classified as direct prime-editing evidence, supporting evidence from other genome-editing platforms, or conceptual application. The strongest translational case currently lies in ex vivo editing of hematopoietic stem and progenitor cells, where target cells are accessible, products can be characterized before infusion, and durable correction can be measured after engraftment. By contrast, solid tumors, HIV reservoirs, and the central nervous system impose more demanding delivery and editing-threshold requirements. Relative to nuclease-mediated CRISPR-Cas9 and base editing, prime editing offers broader sequence flexibility and avoids programmed double-strand breaks, but generally carries a larger delivery burden and remains less clinically mature. Future progress will require standardized outcome reporting, clinically relevant offtarget assessment, head-to-head comparisons with alternative editing platforms, validation in long-term repopulating or disease-relevant cells, scalable manufacturing, and extended in vivo surveillance.