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Notably, EDIT-101 was designed for a permanent edit in post-mitotic photoreceptors with lifelong Cas9 persistence. This review addresses this gap by defining the biological and therapeutic conditions that drive benefit from extended Cas activity while minimizing risk. We will (i) examine relationships between expression window and efficacy across Cas9\/Cas12\/Cas13 modalities, (ii) identify genome-wide off-target liabilities alongside orthogonal assays, and (iii) discuss controllable, self-limiting, and recallable editor platforms. By separating durable edits from persistent nuclease exposure, and by providing validated control levers, this work establishes a generalizable framework for safe, higher-efficacy CRISPR medicines. Furthermore, we highlight key studies in cell lines, murine models, non-human primates, and humans that examine the long-term effects of sustained expression of CRISPR\/Cas systems and discuss the safety and efficacy of such approaches. Current evidence demonstrates promising therapeutic outcomes with manageable safety profiles, although there is a need for continued monitoring as CRISPR\/Cas therapies are increasingly applied in clinical contexts and therapies are developed for broader clinical applications.<\/jats:p>","DOI":"10.3390\/cells15020156","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T11:13:21Z","timestamp":1768475601000},"page":"156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chronic In Vivo CRISPR-Cas Genome Editing: Challenges, Long-Term Safety, and Outlook"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6208-9264","authenticated-orcid":false,"given":"Caroline","family":"Bao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4527-6176","authenticated-orcid":false,"given":"Catherine I.","family":"Channell","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Hsuan","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical University, New Taipei City 252, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4404-2714","authenticated-orcid":false,"given":"Naeem","family":"Sbaiti","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6738-1643","authenticated-orcid":false,"given":"Aykut","family":"Demirkol","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10032, USA"},{"name":"Jonas Children\u2019s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9082-2427","authenticated-orcid":false,"given":"Stephen H.","family":"Tsang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10032, USA"},{"name":"Jonas Children\u2019s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5429","DOI":"10.1128\/jb.169.12.5429-5433.1987","article-title":"Nucleotide Sequence of the Iap Gene, Responsible for Alkaline Phosphatase Isozyme Conversion in Escherichia coli, and Identification of the Gene Product","volume":"169","author":"Ishino","year":"1987","journal-title":"J. Bacteriol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1046\/j.1365-2958.2002.02839.x","article-title":"Identification of Genes That Are Associated with DNA Repeats in Prokaryotes","volume":"43","author":"Jansen","year":"2002","journal-title":"Mol. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s00239-004-0046-3","article-title":"Intervening Sequences of Regularly Spaced Prokaryotic Repeats Derive from Foreign Genetic Elements","volume":"60","author":"Mojica","year":"2005","journal-title":"J. Mol. Evol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1126\/science.1138140","article-title":"CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes","volume":"315","author":"Barrangou","year":"2007","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1126\/science.1159689","article-title":"Small CRISPR RNAs Guide Antiviral Defense in Prokaryotes","volume":"321","author":"Brouns","year":"2008","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nature09523","article-title":"The CRISPR\/Cas Bacterial Immune System Cleaves Bacteriophage and Plasmid DNA","volume":"468","author":"Garneau","year":"2010","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1126\/science.1165771","article-title":"CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA","volume":"322","author":"Marraffini","year":"2008","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zakrzewska, M., and Burmistrz, M. (2023). Mechanisms Regulating the CRISPR-Cas Systems. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1060337"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dela Ahator, S., Liu, Y., Wang, J., and Zhang, L.-H. (2022). The Virulence Factor Regulator and Quorum Sensing Regulate the Type I-F CRISPR-Cas Mediated Horizontal Gene Transfer in Pseudomonas Aeruginosa. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.987656"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1038\/nprot.2014.134","article-title":"Generating Genetically Modified Mice Using CRISPR\/Cas-Mediated Genome Engineering","volume":"9","author":"Yang","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6038","DOI":"10.1093\/nar\/gkv517","article-title":"Regulation of the Type I-F CRISPR-Cas System by CRP-cAMP and GalM Controls Spacer Acquisition and Interference","volume":"43","author":"Patterson","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/15569527.2025.2573463","article-title":"Clinical and Pharmacovigilance Safety Evaluation of LUXTURNA\u00ae (Voretigene Neparvovec-Rzyl)","volume":"44","author":"Simoens","year":"2025","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.mib.2017.05.008","article-title":"Diversity, Classification and Evolution of CRISPR-Cas Systems","volume":"37","author":"Koonin","year":"2017","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.csbj.2020.08.031","article-title":"CRISPR-Cas Systems: Overview, Innovations and Applications in Human Disease Research and Gene Therapy","volume":"18","author":"Xu","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/pcmedi\/pbab014","article-title":"Applications and Challenges of CRISPR-Cas Gene-Editing to Disease Treatment in Clinics","volume":"4","author":"Liu","year":"2021","journal-title":"Precis. Clin. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1099\/mic.0.28048-0","article-title":"Clustered Regularly Interspaced Short Palindrome Repeats (CRISPRs) Have Spacers of Extrachromosomal Origin","volume":"151","author":"Bolotin","year":"2005","journal-title":"Microbiol. Read. Engl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.1225829","article-title":"A Programmable Dual-RNA\u2013Guided DNA Endonuclease in Adaptive Bacterial Immunity","volume":"337","author":"Jinek","year":"2012","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E2579","DOI":"10.1073\/pnas.1208507109","article-title":"Cas9\u2013crRNA Ribonucleoprotein Complex Mediates Specific DNA Cleavage for Adaptive Immunity in Bacteria","volume":"109","author":"Gasiunas","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e264","DOI":"10.1038\/mtna.2015.37","article-title":"Off-Target Effects in CRISPR\/Cas9-Mediated Genome Engineering","volume":"4","author":"Zhang","year":"2015","journal-title":"Mol. Ther.-Nucleic Acids"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102124","DOI":"10.1016\/j.omtn.2024.102124","article-title":"SpCas9-HF1 Enhances Accuracy of Cell Cycle-Dependent Genome Editing by Increasing HDR Efficiency, and by Reducing off-Target Effects and Indel Rates","volume":"35","author":"Matsumoto","year":"2024","journal-title":"Mol. Ther.-Nucleic Acids"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2147\/BTT.S429411","article-title":"Recent Advancements in Reducing the Off-Target Effect of CRISPR-Cas9 Genome Editing","volume":"18","author":"Teshome","year":"2024","journal-title":"Biol. Targets Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/1873-3468.14608","article-title":"Cas9-Geminin and Cdt1-Fused Anti-CRISPR Protein Synergistically Increase Editing Accuracy","volume":"597","author":"Matsumoto","year":"2023","journal-title":"FEBS Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"RP102538","DOI":"10.7554\/eLife.102538.3","article-title":"Flexibility in PAM Recognition Expands DNA Targeting in xCas9","volume":"13","author":"Hossain","year":"2025","journal-title":"eLife"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"(2025, September 21). CRISPR-Cas9 DNA Base-Editing and Prime-Editing. Available online: https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6240.","DOI":"10.3390\/ijms21176240"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1016\/j.ymthe.2023.03.024","article-title":"CRISPR-Cas-Mediated Transcriptional Modulation: The Therapeutic Promises of CRISPRa and CRISPRi","volume":"31","author":"Bendixen","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pattali, R.K., Ornelas, I.J., Nguyen, C.D., Xu, D., Divekar, N.S., and Nu\u00f1ez, J.K. (2024). CRISPRoff Epigenetic Editing for Programmable Gene Silencing in Human Cells without DNA Breaks. bioRxiv.","DOI":"10.1101\/2024.09.09.612111"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/j.cell.2021.03.025","article-title":"Genome-Wide Programmable Transcriptional Memory by CRISPR-Based Epigenome Editing","volume":"184","author":"Chen","year":"2021","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chey, Y.C.J., Gierus, L., Lushington, C., Arudkumar, J.C., Geiger, A.B., Staker, L.G., Robertson, L.J., Pfitzner, C., Kennedy, J.G., and Lee, R.H.B. (2025). Optimal SpCas9- and SaCas9-Mediated Gene Editing by Enhancing gRNA Transcript Levels through Scaffold Poly-T Tract Reduction. BMC Genom., 26.","DOI":"10.1186\/s12864-025-11317-2"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Allen, D., Rosenberg, M., and Hendel, A. (2021). Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells. Front. Genome Ed., 2.","DOI":"10.3389\/fgeed.2020.617910"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.molcel.2018.06.043","article-title":"Kinetic Basis for DNA Target Specificity of CRISPR-Cas12a","volume":"71","author":"Strohkendl","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.1017\/erm.2025.10","article-title":"Advancing CRISPR Genome Editing into Gene Therapy Clinical Trials: Progress and Future Prospects","volume":"27","author":"Cetin","year":"2025","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1038\/s41467-025-57150-9","article-title":"Highly Parallel Profiling of the Activities and Specificities of Cas12a Variants in Human Cells","volume":"16","author":"Chen","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1038\/s41467-024-48012-x","article-title":"Harnessing Noncanonical crRNA for Highly Efficient Genome Editing","volume":"15","author":"Xun","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113777","DOI":"10.1016\/j.celrep.2024.113777","article-title":"Harnessing Noncanonical crRNAs to Improve Functionality of Cas12a Orthologs","volume":"43","author":"Nguyen","year":"2024","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1038\/s41467-022-29227-2","article-title":"Comprehensive Characterization of PTEN Mutational Profile in a Series of 34,129 Colorectal Cancers","volume":"13","author":"Serebriiskii","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1111\/jipb.12944","article-title":"Targeted Mutagenesis in Arabidopsis Thaliana Using CRISPR-Cas12b\/C2c1","volume":"62","author":"Wu","year":"2020","journal-title":"J. Integr. Plant Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Huang, Z., Fang, J., Zhou, M., Gong, Z., and Xiang, T. (2022). CRISPR-Cas13: A New Technology for the Rapid Detection of Pathogenic Microorganisms. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.1011399"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1126\/science.aam9321","article-title":"Nucleic Acid Detection with CRISPR-Cas13a\/C2c2","volume":"356","author":"Gootenberg","year":"2017","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102789","DOI":"10.1016\/j.copbio.2022.102789","article-title":"The Double Life of CRISPR\u2013Cas13","volume":"78","author":"Bot","year":"2022","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.molcel.2021.12.002","article-title":"The CRISPR-Cas Toolbox and Gene Editing Technologies","volume":"82","author":"Liu","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41589-024-01729-8","article-title":"Compact RNA Editors with Natural Miniature Cas13j Nucleases","volume":"21","author":"Li","year":"2025","journal-title":"Nat. Chem. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41587-022-01419-7","article-title":"High-Fidelity Cas13 Variants for Targeted RNA Degradation with Minimal Collateral Effects","volume":"41","author":"Tong","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1126\/science.aax7063","article-title":"A Cytosine Deaminase for Programmable Single-Base RNA Editing","volume":"365","author":"Abudayyeh","year":"2019","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"gkaf181","DOI":"10.1093\/nar\/gkaf181","article-title":"Enhanced or Reversible RNA N6-Methyladenosine Editing by Red\/Far-Red Light Induction","volume":"53","author":"Tang","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41589-024-01593-6","article-title":"Structures, Mechanisms and Applications of RNA-Centric CRISPR\u2013Cas13","volume":"20","author":"Yang","year":"2024","journal-title":"Nat. Chem. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1038\/s41467-024-46412-7","article-title":"dCas13-Mediated Translational Repression for Accurate Gene Silencing in Mammalian Cells","volume":"15","author":"Apostolopoulos","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e26179","DOI":"10.1016\/j.heliyon.2024.e26179","article-title":"CRISPR\/Cas-Based Nucleic Acid Detection Strategies: Trends and Challenges","volume":"10","author":"Zhou","year":"2024","journal-title":"Heliyon"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Li, H., Qiu, Y., Song, B., Quan, X., Zhang, D., Li, X., Yang, J., Liu, X., Zeng, Z., and Jing, J. (2025). Engineering a Photoactivatable A-to-I RNA Base Editor for Gene Therapy in Vivo. Nat. Biotechnol., 1\u201312. Epub ahead of print.","DOI":"10.1038\/s41587-025-02610-2"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4185","DOI":"10.1016\/j.ymthe.2024.10.017","article-title":"Recombinant Adeno-Associated Virus as a Delivery Platform for Ocular Gene Therapy: A Comprehensive Review","volume":"32","author":"Wang","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41392-024-01780-w","article-title":"Adeno-Associated Virus as a Delivery Vector for Gene Therapy of Human Diseases","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Dong, W., and Kantor, B. (2021). Lentiviral Vectors for Delivery of Gene-Editing Systems Based on CRISPR\/Cas: Current State and Perspectives. Viruses, 13.","DOI":"10.3390\/v13071288"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Diakatou, M., Dubois, G., Erkilic, N., Sanjurjo-Soriano, C., Meunier, I., and Kalatzis, V. (2021). Allele-Specific Knockout by CRISPR\/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052607"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1186\/s12951-023-02044-5","article-title":"Emerging Non-Viral Vectors for Gene Delivery","volume":"21","author":"Wang","year":"2023","journal-title":"J. Nanobiotechnol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"114990","DOI":"10.1016\/j.addr.2023.114990","article-title":"Lipid Nanoparticles (LNPs) for in Vivo RNA Delivery and Their Breakthrough Technology for Future Applications","volume":"200","author":"Jeong","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1056\/NEJMoa2107454","article-title":"CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis","volume":"385","author":"Gillmore","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"105834","DOI":"10.1016\/j.ebiom.2025.105834","article-title":"Viral and Non-Viral Vectors in Gene Therapy: Current State and Clinical Perspectives","volume":"118","author":"Geng","year":"2025","journal-title":"eBioMedicine"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9243","DOI":"10.1021\/acsnano.0c04707","article-title":"Delivery of Tissue-Targeted Scalpels: Opportunities and Challenges for In Vivo CRISPR\/Cas-Based Genome Editing","volume":"14","author":"Wei","year":"2020","journal-title":"ACS Nano"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1182\/blood-2011-09-382317","article-title":"Factor IX Expression in Skeletal Muscle of a Severe Hemophilia B Patient 10 Years after AAV-Mediated Gene Transfer","volume":"119","author":"Buchlis","year":"2012","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.tig.2021.02.008","article-title":"DNA Repair Pathway Choices in CRISPR-Cas9 Mediated Genome Editing","volume":"37","author":"Xue","year":"2021","journal-title":"Trends Genet. TIG"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s12033-022-00567-0","article-title":"A Review on the Mechanism and Applications of CRISPR\/Cas9\/Cas12\/Cas13\/Cas14 Proteins Utilized for Genome Engineering","volume":"65","author":"Hillary","year":"2023","journal-title":"Mol. Biotechnol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"102344","DOI":"10.1016\/j.omtn.2024.102344","article-title":"CRISPR-Cas9-Mediated Homology-Directed Repair for Precise Gene Editing","volume":"35","author":"Liao","year":"2024","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nrm.2017.48","article-title":"Non-Homologous DNA End Joining and Alternative Pathways to Double-Strand Break Repair","volume":"18","author":"Chang","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/35006670","article-title":"DNA Repair Protein Ku80 Suppresses Chromosomal Aberrations and Malignant Transformation","volume":"404","author":"Difilippantonio","year":"2000","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/s41467-024-45553-z","article-title":"Structural Role for DNA Ligase IV in Promoting the Fidelity of Non-Homologous End Joining","volume":"15","author":"Stinson","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"24377","DOI":"10.1074\/jbc.M116.752329","article-title":"Different DNA End Configurations Dictate Which NHEJ Components Are Most Important for Joining Efficiency*","volume":"291","author":"Chang","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.tibs.2015.08.006","article-title":"Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway?","volume":"40","author":"Sfeir","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.dnarep.2006.05.028","article-title":"Modeling Oncogenic Translocations: Distinct Roles for Double-Strand Break Repair Pathways in Translocation Formation in Mammalian Cells","volume":"5","author":"Weinstock","year":"2006","journal-title":"DNA Repair"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-981-13-0593-1_2","article-title":"Induction of Chromosomal Translocations with CRISPR-Cas9 and Other Nucleases: Understanding the Repair Mechanisms That Give Rise to Translocations","volume":"1044","author":"Brunet","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41568-022-00488-9","article-title":"Structural Variations in Cancer and the 3D Genome","volume":"22","author":"Dubois","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00439-023-02561-1","article-title":"Unintended CRISPR-Cas9 Editing Outcomes: A Review of the Detection and Prevalence of Structural Variants Generated by Gene-Editing in Human Cells","volume":"142","author":"Hunt","year":"2023","journal-title":"Hum. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/nbt.2623","article-title":"High-Frequency off-Target Mutagenesis Induced by CRISPR-Cas Nucleases in Human Cells","volume":"31","author":"Fu","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1126\/science.1231143","article-title":"Multiplex Genome Engineering Using CRISPR\/Cas Systems","volume":"339","author":"Cong","year":"2013","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"107439","DOI":"10.1016\/j.jbc.2024.107439","article-title":"A Mechanistic Study on the Tolerance of PAM Distal End Mismatch by SpCas9","volume":"300","author":"Dey","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nbt.2916","article-title":"Genome-Wide Analysis Reveals Characteristics of off-Target Sites Bound by the Cas9 Endonuclease","volume":"32","author":"Kuscu","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nbt.2889","article-title":"Genome-Wide Binding of the CRISPR Endonuclease Cas9 in Mammalian Cells","volume":"32","author":"Wu","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/cr.2014.87","article-title":"Genome-Wide Identification of CRISPR\/Cas9 off-Targets in Human Genome","volume":"24","author":"Duan","year":"2014","journal-title":"Cell Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ymthe.2019.09.006","article-title":"Doxycycline-Dependent Self-Inactivation of CRISPR-Cas9 to Temporally Regulate On- and Off-Target Editing","volume":"28","author":"Kelkar","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41586-019-1161-z","article-title":"Transcriptome-Wide off-Target RNA Editing Induced by CRISPR-Guided DNA Base Editors","volume":"569","author":"Zhou","year":"2019","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"100693","DOI":"10.1016\/j.xgen.2024.100693","article-title":"Seed Sequences Mediate Off-Target Activity in the CRISPR-Interference System","volume":"4","author":"Rohatgi","year":"2024","journal-title":"Cell Genom."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1093\/nar\/gkab1131","article-title":"CRISPRroots: On- and off-Target Assessment of RNA-Seq Data in CRISPR\u2013Cas9 Edited Cells","volume":"50","author":"Corsi","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1038\/s41467-019-12449-2","article-title":"High Levels of AAV Vector Integration into CRISPR-Induced DNA Breaks","volume":"10","author":"Hanlon","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_82","first-page":"442","article-title":"Adeno-Associated Virus Vector Integration","volume":"11","author":"Deyle","year":"2009","journal-title":"Curr. Opin. Mol. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1016\/j.ymthe.2022.06.004","article-title":"Evaluating the State of the Science for Adeno-Associated Virus Integration: An Integrated Perspective","volume":"30","author":"Sabatino","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/mt.2016.52","article-title":"Recombinant AAV Integration Is Not Associated with Hepatic Genotoxicity in Nonhuman Primates and Patients","volume":"24","author":"Fronza","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41587-024-02171-w","article-title":"Genome Engineering with Cas9 and AAV Repair Templates Generates Frequent Concatemeric Insertions of Viral Vectors","volume":"43","author":"Suchy","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ewaisha, R., and Anderson, K.S. (2023). Immunogenicity of CRISPR Therapeutics\u2014Critical Considerations for Clinical Translation. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1138596"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.omtm.2018.06.006","article-title":"Prevalence of Pre-Existing Antibodies to CRISPR-Associated Nuclease Cas9 in the USA Population","volume":"10","author":"Simhadri","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/s41591-018-0204-6","article-title":"High Prevalence of Streptococcus Pyogenes Cas9-Reactive T Cells within the Adult Human Population","volume":"25","author":"Wagner","year":"2019","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1038\/s41591-022-01848-6","article-title":"Pre-Existing Adaptive Immunity to the RNA-Editing Enzyme Cas13d in Humans","volume":"28","author":"Tang","year":"2022","journal-title":"Nat. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1101\/gr.231936.117","article-title":"CRISPR RNAs Trigger Innate Immune Responses in Human Cells","volume":"28","author":"Kim","year":"2018","journal-title":"Genome Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1016\/j.ymthe.2025.03.037","article-title":"The Curious Case of AAV Immunology","volume":"33","author":"Keeler","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Ertl, H.C.J. (2022). Immunogenicity and Toxicity of AAV Gene Therapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.975803"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jpeds.2020.11.054","article-title":"Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series","volume":"231","author":"Chand","year":"2021","journal-title":"J. Pediatr."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/S0168-9525(00)02025-4","article-title":"US Gene Therapy in Crisis","volume":"16","year":"2000","journal-title":"Trends Genet. TIG"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/d41573-021-00164-x","article-title":"Gene Therapy Community Grapples with Toxicity Issues, as Pipeline Matures","volume":"20","author":"Mullard","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"7101","DOI":"10.1038\/s41467-021-26714-w","article-title":"Low Immunogenicity of LNP Allows Repeated Administrations of CRISPR-Cas9 mRNA into Skeletal Muscle in Mice","volume":"12","author":"Kenjo","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_97","unstructured":"(2025, September 21). Editas Medicine Nominates EDIT-401, an LDLR-Targeted Medicine, as Lead In Vivo Development Candidate | Editas Medicine. Available online: https:\/\/ir.editasmedicine.com\/news-releases\/news-release-details\/editas-medicine-nominates-edit-401-ldlr-targeted-medicine-lead."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1016\/j.ymthe.2017.05.024","article-title":"Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-Type Lectin-like Molecule 1","volume":"25","author":"Tashiro","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_99","first-page":"38","article-title":"Acute Myeloid Leukemia: A Review","volume":"103","author":"Pelcovits","year":"2020","journal-title":"Rhode Isl. Med. J."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Cora, D., Novo, M., Al-Soufi, W., S\u00e1nchez, L., and Arana, \u00c1.J. (2025). CRISPR\/Cas9 Delivery Systems to Enhance Gene Editing Efficiency. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094420"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1161\/ATVBAHA.122.318839","article-title":"New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol","volume":"43","author":"Meng","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1016\/j.ymthe.2021.02.020","article-title":"Long-Term Stable Reduction of Low-Density Lipoprotein in Nonhuman Primates Following in Vivo Genome Editing of PCSK9","volume":"29","author":"Wang","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1056\/NEJMra2401857","article-title":"Parkinson\u2019s Disease","volume":"391","author":"Tanner","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1038\/s41380-022-01518-6","article-title":"A\u03b2 Profiles Generated by Alzheimer\u2019s Disease Causing PSEN1 Variants Determine the Pathogenicity of the Mutation and Predict Age at Disease Onset","volume":"27","author":"Petit","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1007\/s000180050219","article-title":"Monogenic Determinants of Familial Alzheimer\u2019s Disease: Presenilin-1 Mutations","volume":"54","author":"Kovacs","year":"1998","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"dmm050279","DOI":"10.1242\/dmm.050279","article-title":"Efficient Genetic Editing of Human Intestinal Organoids Using Ribonucleoprotein-Based CRISPR","volume":"16","author":"Adler","year":"2023","journal-title":"Dis. Models Mech."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"101544","DOI":"10.1016\/j.xcrm.2024.101544","article-title":"Prime Editing Functionally Corrects Cystic Fibrosis-Causing CFTR Mutations in Human Organoids and Airway Epithelial Cells","volume":"5","author":"Bulcaen","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Shahin, S., Xu, H., Lu, B., Mercado, A., Jones, M.K., Bakondi, B., and Wang, S. (2022). AAV-CRISPR\/Cas9 Gene Editing Preserves Long-Term Vision in the P23H Rat Model of Autosomal Dominant Retinitis Pigmentosa. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040824"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/j.ymthe.2022.02.010","article-title":"CRISPR Genome Surgery in a Novel Humanized Model for Autosomal Dominant Retinitis Pigmentosa","volume":"30","author":"Wu","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e84065","DOI":"10.7554\/eLife.84065","article-title":"Allele-Specific Gene-Editing Approach for Vision Loss Restoration in RHO-Associated Retinitis Pigmentosa","volume":"12","author":"Liu","year":"2023","journal-title":"eLife"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"14716","DOI":"10.1038\/ncomms14716","article-title":"Nrl Knockdown by AAV-Delivered CRISPR\/Cas9 Prevents Retinal Degeneration in Mice","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e2416827121","DOI":"10.1073\/pnas.2416827121","article-title":"In Vivo Photoreceptor Base Editing Ameliorates Rhodopsin-E150K Autosomal-Recessive Retinitis Pigmentosa in Mice","volume":"121","author":"Du","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"101459","DOI":"10.1016\/j.xcrm.2024.101459","article-title":"CRISPR Editing of Anti-Anemia Drug Target Rescues Independent Preclinical Models of Retinitis Pigmentosa","volume":"5","author":"Nolan","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ymthe.2018.10.009","article-title":"Long-Term Effects of In Vivo Genome Editing in the Mouse Retina Using Campylobacter jejuni Cas9 Expressed via Adeno-Associated Virus","volume":"27","author":"Jo","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1038\/s41591-024-03466-w","article-title":"In Vivo Base Editing Extends Lifespan of a Humanized Mouse Model of Prion Disease","volume":"31","author":"An","year":"2025","journal-title":"Nat. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.stemcr.2014.10.013","article-title":"Precise Correction of the Dystrophin Gene in Duchenne Muscular Dystrophy Patient Induced Pluripotent Stem Cells by TALEN and CRISPR-Cas9","volume":"4","author":"Li","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.1038\/s41467-021-23996-y","article-title":"Efficient Precise in Vivo Base Editing in Adult Dystrophic Mice","volume":"12","author":"Xu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41593-024-01838-6","article-title":"An RNA Editing Strategy Rescues Gene Duplication in a Mouse Model of MECP2 Duplication Syndrome and Nonhuman Primates","volume":"28","author":"Yang","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_119","first-page":"214","article-title":"Application of the Genome Editing Tool CRISPR\/Cas9 in Non-Human Primates","volume":"37","author":"Luo","year":"2016","journal-title":"Zool. Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"101121","DOI":"10.1016\/j.omtm.2023.101121","article-title":"Efficient Long-Term Multilineage Engraftment of CD33-Edited Hematopoietic Stem\/Progenitor Cells in Nonhuman Primates","volume":"31","author":"Petty","year":"2023","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.cell.2018.05.013","article-title":"Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia","volume":"173","author":"Kim","year":"2018","journal-title":"Cell"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1016\/j.ymthe.2022.07.010","article-title":"A Precise and Efficient Adenine Base Editor","volume":"30","author":"Tu","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41586-021-03534-y","article-title":"In Vivo CRISPR Base Editing of PCSK9 Durably Lowers Cholesterol in Primates","volume":"593","author":"Musunuru","year":"2021","journal-title":"Nature"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"469","DOI":"10.24272\/j.issn.2095-8137.2021.023","article-title":"PINK1 Gene Mutation by Pair Truncated sgRNA\/Cas9-D10A in Cynomolgus Monkeys","volume":"42","author":"Chen","year":"2021","journal-title":"Zool. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5492","DOI":"10.1002\/alz.14046","article-title":"Early Blood Immune Molecular Alterations in Cynomolgus Monkeys with a PSEN1 Mutation Causing Familial Alzheimer\u2019s Disease","volume":"20","author":"Li","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"118496","DOI":"10.1016\/j.atherosclerosis.2024.118496","article-title":"An Investigational in Vivo Base Editing Medicine Targeting ANGPTL3, VERVE-201, Achieves Precise and Durable Liver Editing in Nonclinical Studies","volume":"395","author":"Lee","year":"2024","journal-title":"Atherosclerosis"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1126\/science.270.5239.1158","article-title":"Unraveling Immune Privilege","volume":"270","author":"Streilein","year":"1995","journal-title":"Science"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Irigoyen, C., Amenabar Alonso, A., Sanchez-Molina, J., Rodr\u00edguez-Hidalgo, M., Lara-L\u00f3pez, A., and Ruiz-Ederra, J. (2022). Subretinal Injection Techniques for Retinal Disease: A Review. J. Clin. Med., 11.","DOI":"10.3390\/jcm11164717"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/s41467-022-28674-1","article-title":"Investigation of Cas9 Antibodies in the Human Eye","volume":"13","author":"Toral","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_130","unstructured":"(2025, November 01). Safety and Efficacy of MCO-010 Optogenetic Therapy in Patients with Stargardt Disease in USA (STARLIGHT): An Open-Label Multi-Center Ph2 Trial\u2014PMC, Available online: https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC12362400\/."},{"key":"ref_131","unstructured":"Editas Medicine, Inc. (2025, November 01). Open-Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Efficacy of EDIT-101 in Adult and Pediatric Participants with Leber Congenital Amaurosis Type 10 (LCA10), with Centrosomal Protein 290 (CEP290)-Related Retinal Degeneration Caused by a Compound Heterozygous or Homozygous Mutation Involving c.2991+1655A>G in Intron 26 (IVS26) of the CEP290 Gene (*LCA10-IVS26*), Available online: https:\/\/clinicaltrials.gov\/study\/NCT03872479."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1056\/NEJMoa2309915","article-title":"Gene Editing for CEP290-Associated Retinal Degeneration","volume":"390","author":"Pierce","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41591-018-0327-9","article-title":"Development of a Gene-Editing Approach to Restore Vision Loss in Leber Congenital Amaurosis Type 10","volume":"25","author":"Maeder","year":"2019","journal-title":"Nat. Med."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1167\/iovs.64.3.23","article-title":"Phenotypic Variability of Retinal Disease Among a Cohort of Patients with Variants in the CLN Genes","volume":"64","author":"Kolesnikova","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Wei, A., Yin, D., Zhai, Z., Ling, S., Le, H., Tian, L., Xu, J., Paludan, S.R., Cai, Y., and Hong, J. (2023). In Vivo CRISPR Gene Editing in Patients with Herpes Stromal Keratitis. medRxiv, medRxiv:2023.02.21.23285822.","DOI":"10.1101\/2023.02.21.23285822"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1056\/NEJMoa2412309","article-title":"CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy","volume":"391","author":"Fontana","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_137","unstructured":"(2025, September 28). Intellia Therapeutics Announces First Quarter 2025 Financial Results and Highlights Recent Company Progress\u2014Intellia Therapeutics. Available online: https:\/\/ir.intelliatx.com\/news-releases\/news-release-details\/intellia-therapeutics-announces-first-quarter-2025-financial."},{"key":"ref_138","unstructured":"Verve Therapeutics, Inc. (2025, December 22). Open-Label, Phase 1b, Single-Ascending Dose and Optional Re Dosing Study to Evaluate the Safety of VERVE-101 Administered to Patients with Heterozygous Familial Hypercholesterolemia, Atherosclerotic Cardiovascular Disease, and Uncontrolled Hypercholesterolemia, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05398029."},{"key":"ref_139","unstructured":"Verve Therapeutics (2024). Verve Therapeutics Announces Updates on Its PCSK9 Program, Verve Therapeutics."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Vafai, S., Karsten, V., Jensen, C., Falzone, R., Lister, T., Stolz, L., Khera, A., Kathiresan, S., Bellinger, A., and Fiedorek, F. (2024). Design of Heart-2: A Phase 1b Clinical Trial of VERVE-102, an in Vivo Base Editing Medicine Delivered by a GalNAc-LNP and Targeting PCSK9 to Durably Lower LDL Cholesterol. Circulation, Lippincott Williams & WilkinsHagerstown.","DOI":"10.1161\/circ.150.suppl_1.4139206"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1056\/NEJMoa2031054","article-title":"CRISPR-Cas9 Gene Editing for Sickle Cell Disease and \u03b2-Thalassemia","volume":"384","author":"Frangoul","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1089\/jop.2024.0084","article-title":"Efficacy of Intravitreal Multi-Characteristic Opsin (MCO-010) Optogenetic Gene Therapy in a Mouse Model of Leber Congenital Amaurosis","volume":"40","author":"Dibas","year":"2024","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_143","unstructured":"(2025, November 14). GenSight Biologics Announces 1 Year Safety Data and Efficacy Signals from PIONEER Phase I\/II Clinical Trial of GS030, an Optogenetic Treatment Candidate for Retinitis Pigmentosa\u2014GenSight Biologics. Available online: https:\/\/www.gensight-biologics.com\/2023\/02\/13\/gensight-biologics-announces-1-year-safety-data-and-efficacy-signals-from-pioneer-phase-i-ii-clinical-trial-of-gs030-an-optogenetic-treatment-candidate-for-retinitis-pigmentosa\/."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.omtn.2018.07.010","article-title":"Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models","volume":"12","author":"Dulla","year":"2018","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1056\/NEJMoa2300757","article-title":"Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis","volume":"389","author":"Maurer","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2409134","article-title":"Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy","volume":"392","author":"Fontana","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1056\/NEJMoa1716793","article-title":"Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis","volume":"379","author":"Benson","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1001\/jama.2023.18688","article-title":"Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy","volume":"330","author":"Coelho","year":"2023","journal-title":"JAMA"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa2402478","article-title":"Efficacy and Safety of Donidalorsen for Hereditary Angioedema","volume":"391","author":"Riedl","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/S0140-6736(23)00350-1","article-title":"Efficacy and Safety of Garadacimab, a Factor XIIa Inhibitor for Hereditary Angioedema Prevention (VANGUARD): A Global, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial","volume":"401","author":"Craig","year":"2023","journal-title":"Lancet"},{"key":"ref_151","unstructured":"(2025, December 27). A Phase 1\/2 Open-Label, Dose-Escalation Study to Determine the Safety Tolerability & Efficacy of BMN 331 an AAV Vector-Mediated Gene Transfer of Human SERPING1 Gene in Subjects with HAE Due to Human C1-INH Deficiency, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05121376."},{"key":"ref_152","unstructured":"Verve Therapeutics, Inc. (2025, November 12). A Phase 1b Single Ascending Dose Study to Evaluate the Safety of VERVE-201 in Patients with Refractory Hyperlipidemia, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06451770."},{"key":"ref_153","unstructured":"(2025, November 14). CRISPR Therapeutics Reports Positive Additional Phase 1 Data for CTX310TM Targeting ANGPTL3 and Provides Update on In Vivo Cardiovascular Pipeline. Available online: https:\/\/crisprtx.com\/about-us\/press-releases-and-presentations\/crispr-therapeutics-reports-positive-additional-phase-1-data-for-ctx310-targeting-angptl3-and-provides-update-on-in-vivo-cardiovascular-pipeline."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1056\/NEJMoa1912387","article-title":"Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol","volume":"382","author":"Ray","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_155","unstructured":"Ikaria Bioscience Pty Ltd. (2025, December 27). A Phase 1, Randomized, Single-Blinded, Placebo-Controlled, Single-Ascending-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of RN0191 in Adult Subjects with Elevated Low-Density Lipoprotein-Cholesterol, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05905068."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJMoa2404147","article-title":"Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia","volume":"391","author":"Rosenson","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.1093\/eurheartj\/ehaa689","article-title":"Vupanorsen, an N-Acetyl Galactosamine-Conjugated Antisense Drug to ANGPTL3 mRNA, Lowers Triglycerides and Atherogenic Lipoproteins in Patients with Diabetes, Hepatic Steatosis, and Hypertriglyceridaemia","volume":"41","author":"Gaudet","year":"2020","journal-title":"Eur. Heart J."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T06:01:02Z","timestamp":1768629662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,15]]},"references-count":157,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020156"],"URL":"https:\/\/doi.org\/10.3390\/cells15020156","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,15]]}}}