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This \u201csearch\u2010and\u2010replace\u201d technology employs a Cas9 nickase\u2013reverse transcriptase fusion protein, guided by a PE guide RNA (pegRNA), to directly install specified edits including all 12 base\u2010to\u2010base conversions and targeted insertions\/deletions with high fidelity. Since its introduction, PE systems have undergone rapid evolution (e.g., PE2\u2010PE6, PEmax), markedly improving editing efficiency, product purity, and targeting scope. Although PE efficacy is context dependent, influenced by pegRNA design, cellular milieu, and DNA repair pathway engagement, ongoing research focuses on comprehensive system optimization. These efforts include engineering the Cas9 nickase and reverse transcriptase components for enhanced performance and processivity, alongside developing improved pegRNA architectures and chemical modifications to increase their stability and editing efficiency. Furthermore, strategies to modulate the cellular environment, such as transiently altering DNA repair pathway activities, particularly mismatch repair, are being explored to boost the accuracy and yield of precise edits. PE holds substantial promise for basic research, including precise disease modeling, and has demonstrated successful correction of pathogenic mutations in preclinical models of various genetic disorders like sickle cell disease, cystic fibrosis, and inherited retinal diseases. A significant milestone was the US Food and Drug Administration's granting of Investigational New Drug (IND) clearance for the first clinical trial of PM359, a therapeutic based on PE. This agent employs an ex\u00a0vivo strategy, correcting the\n                    <jats:italic>NCF1<\/jats:italic>\n                    gene in patient\u2010derived hematopoietic stem cells for the treatment of chronic granulomatous disease. Despite considerable progress, unlocking the complete therapeutic promise of PE requires overcoming significant hurdles, particularly in developing effective in\u00a0vivo delivery systems for its sizable components, with ongoing research actively investigating diverse viral and nonviral approaches. The translation of this versatile platform into transformative precision gene therapies is critically dependent upon its continued responsible advancement under robust ethical and regulatory oversight.\n                  <\/jats:p>","DOI":"10.1002\/jgm.70040","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:19Z","timestamp":1759449619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Prime Editing: The Next Frontier in Precision Gene Therapy"],"prefix":"10.1002","volume":"27","author":[{"given":"Melike","family":"Aliciaslan","sequence":"first","affiliation":[{"name":"Department of Gene and Cell Therapy Akdeniz University, Faculty of Medicine  Antalya Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezgi","family":"Erbasan","sequence":"additional","affiliation":[{"name":"Department of Gene and Cell Therapy Akdeniz University, Faculty of Medicine  Antalya Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulya","family":"Erendor","sequence":"additional","affiliation":[{"name":"Department of Gene and Cell Therapy Akdeniz University, Faculty of Medicine  Antalya Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-5678","authenticated-orcid":false,"given":"Salih","family":"Sanlioglu","sequence":"additional","affiliation":[{"name":"Department of Gene and Cell Therapy Akdeniz University, Faculty of Medicine  Antalya Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70056"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2025.10"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1225829"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.4252\/wjsc.v13.i6.485"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/5584_2022_746"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071608"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2023.04.012"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000940"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17946"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24644"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.07.021"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0059-1"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1711-4"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1039315"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14040277"},{"key":"e_1_2_13_17_1","unstructured":"addGene \u201cPrime Editing: Adding Precision and Flexibility to CRISPR Editing \u201daddgene Blog 2025 https:\/\/blog.addgene.org\/prime\u2010editing\u2010crisp\u2010cas\u2010reverse\u2010transcriptase."},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.018"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13808"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01039-7"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12040536"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-022-00724-4"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12033-022-00639-1"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.202200032"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/crispr.2022.0084"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.039"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07259-6"},{"key":"e_1_2_13_28_1","article-title":"Engineered Prime Editors With Minimal Genomic Errors","author":"Chauhan V. 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