{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:15:41Z","timestamp":1791346541161,"version":"4.3.1"},"reference-count":215,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012528","name":"Kazan Federal University","doi-asserted-by":"crossref","award":["FZSM-2026-0022"],"award-info":[{"award-number":["FZSM-2026-0022"]}],"id":[{"id":"10.13039\/501100012528","id-type":"DOI","asserted-by":"crossref"}]},{"award":["FZSM-2026-0022"],"award-info":[{"award-number":["FZSM-2026-0022"]}],"id":[{"id":"https:\/\/ror.org\/05256ym39","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adeno-associated viral (AAV) vectors have established themselves as a promising platform for genetic material delivery in clinical practice, evidenced by regulatory approval of multiple therapeutics. Despite proven therapeutic efficacy, safety concerns remain a critical limitation requiring systematic analysis. This review analyzes clinical data to identify mechanisms of toxicity, clinical risks, and strategies for their minimization in AAV gene therapy. The study examines dose-dependent toxicity, immune responses, and organ-specific burdens associated with systemic and local administration routes. Analysis reveals a clear correlation between systemic delivery efficacy and dose-dependent toxicity, with principal mechanisms including capsid-directed immune responses, hepatic burden, and complement system activation leading to thrombotic microangiopathy. Key determinants of the safety profile include pre-existing neutralizing antibodies, vector dose, serotype selection, and patient baseline conditions. Contemporary strategies for toxicity minimization are evolving from reactive management toward proactive risk mitigation, including prophylactic immunosuppressive regimens, vector engineering to alter tropism or reduce immunogenicity, and rigorous post-infusion monitoring. Integration of improved vector constructs, rational immunosuppressive regimens, and rigorous post-infusion surveillance has the potential to expand the therapeutic window of AAV-based gene therapy, achieving an optimal balance between efficacy and safety for a broader patient population.<\/jats:p>","DOI":"10.3390\/ijms27114818","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:31:56Z","timestamp":1779885116000},"page":"4818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Safety of Adeno-Associated Viral Vectors in Gene Therapy: Mechanisms of Toxicity, Clinical Risks, and Strategies for Their Minimization"],"prefix":"10.3390","volume":"27","author":[{"given":"Tatiana S.","family":"Tsaregorodtseva","sequence":"first","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Radyukhina","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9152-2338","authenticated-orcid":false,"given":"Aisylu I.","family":"Ayupova","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8776-3662","authenticated-orcid":false,"given":"Valeriya V.","family":"Solovyeva","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert A.","family":"Sufianov","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119991 Moscow, Russia"},{"name":"The Research and Educational Institute of Neurosurgery, Peoples\u2019 Friendship University of Russia, 117198 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina Z.","family":"Sufianova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Tyumen State Medical University, 625023 Tyumen, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9427-5739","authenticated-orcid":false,"given":"Albert A.","family":"Rizvanov","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia"},{"name":"Division of Medical and Biological Sciences, Academy of Sciences of the Republic of Tatarstan, 420111 Kazan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1146\/annurev-neuro-111020-100834","article-title":"Adeno-Associated Virus Toolkit to Target Diverse Brain Cells","volume":"45","author":"Challis","year":"2022","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lopez-Gordo, E., Chamberlain, K., Riyad, J.M., Kohlbrenner, E., and Weber, T. (2024). Natural Adeno-Associated Virus Serotypes and Engineered Adeno-Associated Virus Capsid Variants: Tropism Differences and Mechanistic Insights. Viruses, 16, Correction in Viruses\u00a02024, 16, 1366. https:\/\/doi.org\/10.3390\/v16091366.","DOI":"10.3390\/v16091366"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1016\/j.ymthe.2022.03.004","article-title":"Durability of Transgene Expression after rAAV Gene Therapy","volume":"30","author":"Muhuri","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1016\/j.ymthe.2025.03.064","article-title":"AAV Vector Development, Back to the Future","volume":"33","author":"Song","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zwi-Dantsis, L., Mohamed, S., Massaro, G., and Moeendarbary, E. (2025). Adeno-Associated Virus Vectors: Principles, Practices, and Prospects in Gene Therapy. Viruses, 17.","DOI":"10.3390\/v17020239"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Beloukhova, M.I., Lukashev, A.N., Volchkov, P.Y., Zamyatnin, A.A., and Deviatkin, A.A. (2022). Robust AAV Genotyping Based on Genetic Distances in Rep Gene That Are Maintained by Ubiquitous Recombination. Viruses, 14.","DOI":"10.3390\/v14051038"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1146\/annurev-virology-031413-085355","article-title":"AAV-Mediated Gene Therapy for Research and Therapeutic Purposes","volume":"1","author":"Samulski","year":"2014","journal-title":"Annu. Rev. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1089\/hum.2020.29120.bca","article-title":"My Pathway to Adeno-Associated Virus and Adeno-Associated Virus Gene Therapy: A Personal Perspective","volume":"31","author":"Carter","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1038\/mt.2013.226","article-title":"Birth of a New Therapeutic Platform: 47 Years of Adeno-Associated Virus Biology from Virus Discovery to Licensed Gene Therapy","volume":"21","author":"Flotte","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Issa, S.S., Shaimardanova, A.A., Solovyeva, V.V., and Rizvanov, A.A. (2023). Various AAV Serotypes and Their Applications in Gene Therapy: An Overview. Cells, 12.","DOI":"10.3390\/cells12050785"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/hum.2015.025","article-title":"Adeno-Associated Virus at 50: A Golden Anniversary of Discovery, Research, and Gene Therapy Success\u2014A Personal Perspective","volume":"26","author":"Hastie","year":"2015","journal-title":"Hum. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1089\/humc.2013.087","article-title":"Lessons Learned from the Clinical Development and Market Authorization of Glybera","volume":"24","author":"Bryant","year":"2013","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11040","DOI":"10.1128\/JVI.01056-06","article-title":"Adeno-Associated Virus Type 2 Capsids with Externalized VP1\/VP2 Trafficking Domains Are Generated Prior to Passage through the Cytoplasm and Are Maintained until Uncoating Occurs in the Nucleus","volume":"80","author":"Sonntag","year":"2006","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.chom.2011.10.014","article-title":"Adeno-Associated Virus 2 Infection Requires Endocytosis through the CLIC\/GEEC Pathway","volume":"10","author":"Nonnenmacher","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1128\/JVI.74.6.2777-2785.2000","article-title":"Infectious Entry Pathway of Adeno-Associated Virus and Adeno-Associated Virus Vectors","volume":"74","author":"Bartlett","year":"2000","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9163","DOI":"10.1128\/JVI.00282-12","article-title":"Impact of VP1-Specific Protein Sequence Motifs on Adeno-Associated Virus Type 2 Intracellular Trafficking and Nuclear Entry","volume":"86","author":"Porwal","year":"2012","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-Associated Virus Vector as a Platform for Gene Therapy Delivery","volume":"18","author":"Wang","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1182\/blood.2023022589","article-title":"Vector Integration and Fate in the Hemophilia Dog Liver Multiple Years after AAV-FVIII Gene Transfer","volume":"143","author":"Batty","year":"2024","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7875","DOI":"10.1128\/JVI.00649-08","article-title":"Adeno-Associated Virus Vector Genomes Persist as Episomal Chromatin in Primate Muscle","volume":"82","author":"Nowrouzi","year":"2008","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e70127","DOI":"10.1111\/cpr.70127","article-title":"Identification and Phylogenetic Characterisation of Novel Adeno-Associated Virus Capsids in Non-Human Primate Tissues","volume":"59","author":"Zhu","year":"2025","journal-title":"Cell Prolif."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hildyard, J.C.W., and Piercy, R.J. (2023). When Size Really Matters: The Eccentricities of Dystrophin Transcription and the Hazards of Quantifying mRNA from Very Long Genes. Biomedicines, 11.","DOI":"10.20944\/preprints202306.2167.v1"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mendell, J.R., Shieh, P.B., McDonald, C.M., Sahenk, Z., Lehman, K.J., Lowes, L.P., Reash, N.F., Iammarino, M.A., Alfano, L.N., and Sabo, B. (2023). Expression of SRP-9001 Dystrophin and Stabilization of Motor Function up to 2 Years Post-Treatment with Delandistrogene Moxeparvovec Gene Therapy in Individuals with Duchenne Muscular Dystrophy. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1167762"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Uddin, F., Rudin, C.M., and Sen, T. (2020). CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.01387"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ymgme.2003.08.016","article-title":"Fatal Systemic Inflammatory Response Syndrome in a Ornithine Transcarbamylase Deficient Patient Following Adenoviral Gene Transfer","volume":"80","author":"Raper","year":"2003","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1089\/hum.2018.015","article-title":"Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN","volume":"29","author":"Hinderer","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/d41573-021-00017-7","article-title":"The Clinical Landscape for AAV Gene Therapies","volume":"20","author":"Kuzmin","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s40265-014-0339-9","article-title":"Alipogene Tiparvovec: A Review of Its Use in Adults with Familial Lipoprotein Lipase Deficiency","volume":"75","author":"Scott","year":"2015","journal-title":"Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1097\/MOL.0b013e3283555a7e","article-title":"Gene Therapy for Lipoprotein Lipase Deficiency","volume":"23","author":"Gaudet","year":"2012","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_31","unstructured":"European Medicines Agency (EMA) (2026, March 25). Glybera. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/glybera."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yu, T.T.L., Gupta, P., Ronfard, V., Vert\u00e8s, A.A., and Bayon, Y. (2018). Recent Progress in European Advanced Therapy Medicinal Products and Beyond. Front. Bioeng. Biotechnol., 6.","DOI":"10.3389\/fbioe.2018.00130"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1080\/08164622.2025.2457429","article-title":"Evaluating Ocular Health in Retinal Gene Therapies","volume":"108","author":"Kwok","year":"2025","journal-title":"Clin. Exp. Optom."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0140-6736(17)31868-8","article-title":"Efficacy and Safety of Voretigene Neparvovec (AAV2-hRPE65v2) in Patients with RPE65-Mediated Inherited Retinal Dystrophy: A Randomised, Controlled, Open-Label, Phase 3 Trial","volume":"390","author":"Russell","year":"2017","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S1474-4422(21)00001-6","article-title":"Onasemnogene Abeparvovec Gene Therapy for Symptomatic Infantile-Onset Spinal Muscular Atrophy in Patients with Two Copies of SMN2 (STR1VE): An Open-Label, Single-Arm, Multicentre, Phase 3 Trial","volume":"20","author":"Day","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1182\/bloodadvances.2019000811","article-title":"Etranacogene Dezaparvovec (AMT-061 Phase 2b): Normal\/near Normal FIX Activity and Bleed Cessation in Hemophilia B","volume":"3","author":"Giermasz","year":"2019","journal-title":"Blood Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"559","DOI":"10.2147\/JBM.S371438","article-title":"Gene Therapy and Hemophilia: Where Do We Go from Here?","volume":"13","author":"Bolous","year":"2022","journal-title":"J. Blood Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5179","DOI":"10.1182\/bloodadvances.2023011847","article-title":"Roctavian Gene Therapy for Hemophilia A","volume":"8","author":"Small","year":"2024","journal-title":"Blood Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/ana.26755","article-title":"Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged \u22654 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR)","volume":"94","author":"Zaidman","year":"2023","journal-title":"Ann. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/mus.27955","article-title":"Long-Term Safety and Functional Outcomes of Delandistrogene Moxeparvovec Gene Therapy in Patients with Duchenne Muscular Dystrophy: A Phase 1\/2a Nonrandomized Trial","volume":"69","author":"Mendell","year":"2024","journal-title":"Muscle Nerve"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41591-024-03304-z","article-title":"AAV Gene Therapy for Duchenne Muscular Dystrophy: The EMBARK Phase 3 Randomized Trial","volume":"31","author":"Mendell","year":"2025","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/jimd.12637","article-title":"Liver Directed Adeno-Associated Viral Vectors to Treat Metabolic Disease","volume":"47","author":"Chuecos","year":"2024","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Egorova, T., Starikova, A., and Polikarpova, A. (2025). Emerging Technologies Tackling Adeno-Associated Viruses (AAV) Immunogenicity in Gene Therapy Applications. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17111492"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e0295725","DOI":"10.1128\/mbio.02957-25","article-title":"mGem: AAV, from Almost a Virus to an Awesome Vector-or Is It?","volume":"17","author":"Srivastava","year":"2026","journal-title":"mBio"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Mietzsch, M., Jose, A., Chipman, P., Bhattacharya, N., Daneshparvar, N., McKenna, R., and Agbandje-McKenna, M. (2021). Completion of the AAV Structural Atlas: Serotype Capsid Structures Reveals Clade-Specific Features. Viruses, 13.","DOI":"10.3390\/v13010101"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.7150\/thno.89380","article-title":"Understanding AAV Vector Immunogenicity: From Particle to Patient","volume":"14","author":"Dhungel","year":"2024","journal-title":"Theranostics"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Tsaregorodtseva, T.S., Gubaidullina, A.A., Kayumova, B.R., Shaimardanova, A.A., Issa, S.S., Solovyeva, V.V., Sufianov, A.A., Sufianova, G.Z., and Rizvanov, A.A. (2025). Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115224"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wang, X., Klann, P.J., Wiedtke, E., Sano, Y., Fischer, N., Schiller, L., Elfert, A., G\u00fcttsches, A.-K., Weyen, U., and Grimm, D. (2024). Seroprevalence of Binding and Neutralizing Antibodies against 18 Adeno-Associated Virus Types in Patients with Neuromuscular Disorders. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1450858"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1038\/mt.2016.61","article-title":"Superior In Vivo Transduction of Human Hepatocytes Using Engineered AAV3 Capsid","volume":"24","author":"Vercauteren","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/s41434-020-0140-1","article-title":"AAV3-miRNA Vectors for Growth Suppression of Human Hepatocellular Carcinoma Cells in Vitro and Human Liver Tumors in a Murine Xenograft Model in Vivo","volume":"28","author":"Yin","year":"2021","journal-title":"Gene Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.ymthe.2025.01.041","article-title":"A Comprehensive Atlas of AAV Tropism in the Mouse","volume":"33","author":"Walkey","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.1016\/S1525-0016(16)33911-9","article-title":"302. Combinatorial Engineering of a Receptor Footprint on AAV Serotype 4 Yields Novel Vectors","volume":"23","author":"Albright","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"101337","DOI":"10.1016\/j.omtm.2024.101337","article-title":"Optimal Different Adeno-Associated Virus Capsid\/Promoter Combinations to Target Specific Cell Types in the Common Marmoset Cerebral Cortex","volume":"32","author":"Matsuzaki","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Pietersz, K.L., Plessis, F.D., Pouw, S.M., Liefhebber, J.M., van Deventer, S.J., Martens, G.J.M., Konstantinova, P.S., and Blits, B. (2021). PhP.B Enhanced Adeno-Associated Virus Mediated-Expression Following Systemic Delivery or Direct Brain Administration. Front. Bioeng. Biotechnol., 9.","DOI":"10.3389\/fbioe.2021.679483"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101532","DOI":"10.1016\/j.omtm.2025.101532","article-title":"AAV6 Vectors Provide Superior Gene Transfer Compared to AAV9 Vectors Following Intramyocardial Administration","volume":"33","author":"Wang","year":"2025","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Boychenko, S., Abdullina, A., Laktyushkin, V.S., Brovin, A., and Egorov, A.D. (2024). Assessment of Adipocyte Transduction Using Different AAV Capsid Variants. Pharmaceuticals, 17.","DOI":"10.20944\/preprints202408.0199.v1"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11854","DOI":"10.1073\/pnas.182412299","article-title":"Novel Adeno-Associated Viruses from Rhesus Monkeys as Vectors for Human Gene Therapy","volume":"99","author":"Gao","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Bhadury, R., Athar, M., Mishra, P., Gogoi, C., Sharma, S., and Ghorpade, D.S. (2025). Development and Validation of AAV-Mediated Liver, Liver-VAT, and Liver-Brain SORT and Therapeutic Regulation of FASN in Hepatic De Novo Lipogenesis. Cells, 14.","DOI":"10.3390\/cells14050372"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41434-021-00230-4","article-title":"Liver Targeting with rAAV7: Balancing Tropism with Immune Profiles","volume":"28","author":"Flotte","year":"2021","journal-title":"Gene Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e1375","DOI":"10.1002\/cti2.1375","article-title":"Optimising the IgG-Degrading Enzyme Treatment Regimen for Enhanced Adeno-Associated Virus Transduction in the Presence of Neutralising Antibodies","volume":"11","author":"Hommel","year":"2022","journal-title":"Clin. Transl. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1056\/NEJMoa1407309","article-title":"Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B","volume":"371","author":"Nathwani","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"101451","DOI":"10.1016\/j.omtm.2025.101451","article-title":"AAV Capsids Target Muscle-Resident Cells with Different Efficiencies\u2014A Comparative Study between AAV8, AAVMYO, and AAVMYO2","volume":"33","author":"McGowan","year":"2025","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Voznesenskaya, A., Berggren, P.-O., and Ilegems, E. (2023). Sustained Heterologous Gene Expression in Pancreatic Islet Organoids Using Adeno-Associated Virus Serotype 8. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1147244"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/s41551-022-00938-7","article-title":"Variants of the Adeno-Associated Virus Serotype 9 with Enhanced Penetration of the Blood-Brain Barrier in Rodents and Primates","volume":"6","author":"Yao","year":"2022","journal-title":"Nat. Biomed. Eng."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mullagulova, A., Shaimardanova, A., Solovyeva, V., Mukhamedshina, Y., Chulpanova, D., Kostennikov, A., Issa, S., and Rizvanov, A. (2023). Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119204"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e00568","DOI":"10.1016\/j.neurot.2025.e00568","article-title":"A Dose Escalation and Safety Study of AAVrh10-Mediated Schwann Cell-Targeted Gene Therapy for CMT1X","volume":"22","author":"Christou","year":"2025","journal-title":"Neurotherapeutics"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.jtos.2024.09.010","article-title":"Preventing and Treating Neurotrophic Keratopathy by a Single Intrastromal Injection of AAV-Mediated Gene Therapy","volume":"34","author":"Cong","year":"2024","journal-title":"Ocul. Surf."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"23358","DOI":"10.1038\/s41598-021-02694-1","article-title":"Efficacy of AAV Serotypes to Target Schwann Cells after Intrathecal and Intravenous Delivery","volume":"11","author":"Kagiava","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5792","DOI":"10.1167\/iovs.17-22473","article-title":"Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates","volume":"58","author":"Seitz","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Shen, W., Liu, S., and Ou, L. (2022). rAAV Immunogenicity, Toxicity, and Durability in 255 Clinical Trials: A Meta-Analysis. Front. Immunol., 13, Erratum in Front. Immunol.\u00a02023, 13, 1104646. https:\/\/doi.org\/10.3389\/fimmu.2022.1104646.","DOI":"10.3389\/fimmu.2022.1001263"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.xphs.2023.08.023","article-title":"Pharmacokinetics of AAV9 Mediated Trastuzumab Expression in Rat Brain Following Systemic and Local Administration","volume":"113","author":"Chowdhury","year":"2024","journal-title":"J. Pharm. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ronzitti, G., Gross, D.-A., and Mingozzi, F. (2020). Human Immune Responses to Adeno-Associated Virus (AAV) Vectors. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00670"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"S\u0142yk, \u017b., Stachowiak, N., and Ma\u0142ecki, M. (2024). Recombinant Adeno-Associated Virus Vectors for Gene Therapy of the Central Nervous System: Delivery Routes and Clinical Aspects. Biomedicines, 12.","DOI":"10.3390\/biomedicines12071523"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1208\/s12248-021-00678-7","article-title":"The Perspective of DMPK on Recombinant Adeno-Associated Virus-Based Gene Therapy: Past Learning, Current Support, and Future Contribution","volume":"24","author":"Chen","year":"2022","journal-title":"AAPS J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e210268","DOI":"10.1212\/WNL.0000000000210268","article-title":"Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients with Spinal Muscular Atrophy: The Phase 3b SMART Study","volume":"104","author":"McMillan","year":"2025","journal-title":"Neurology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/S1474-4422(21)00251-9","article-title":"Onasemnogene Abeparvovec Gene Therapy for Symptomatic Infantile-Onset Spinal Muscular Atrophy Type 1 (STR1VE-EU): An Open-Label, Single-Arm, Multicentre, Phase 3 Trial","volume":"20","author":"Mercuri","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"351","DOI":"10.3233\/JHD-229006","article-title":"Huntington\u2019s Disease Clinical Trials Corner: November 2022","volume":"11","author":"Tabrizi","year":"2022","journal-title":"J. Huntingt. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1136\/bjo-2024-326480","article-title":"Safety and Vision Outcomes of Subretinal Gene Supplementation Therapy in PDE6A-Associated Retinitis Pigmentosa: A Non-Randomised Controlled Trial","volume":"110","author":"Reichel","year":"2026","journal-title":"Br. J. Ophthalmol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s40259-020-00453-8","article-title":"Focused Update on AAV-Based Gene Therapy Clinical Trials for Inherited Retinal Degeneration","volume":"34","author":"Basiri","year":"2020","journal-title":"BioDrugs"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1056\/NEJMoa2414783","article-title":"Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B","volume":"392","author":"Reiss","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/hae.15121","article-title":"A Phase 1\/2 Safety and Efficacy Study of TAK-754 Gene Therapy: The Challenge of Achieving Durable Factor VIII Expression in Haemophilia A Clinical Trials","volume":"31","author":"Chapin","year":"2025","journal-title":"Haemophilia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S1474-4422(26)00036-0","article-title":"Safety and Efficacy of Fordadistrogene Movaparvovec in Ambulatory Participants with Duchenne Muscular Dystrophy (CIFFREO): A Phase 3, Double-Blind, Randomised, Placebo-Controlled Study","volume":"25","author":"Muntoni","year":"2026","journal-title":"Lancet Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1038\/s41591-025-03750-3","article-title":"AAV Mini-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy: A Phase 1b Trial","volume":"31","author":"Butterfield","year":"2025","journal-title":"Nat. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1378\/chest.125.2.509","article-title":"Repeated Adeno-Associated Virus Serotype 2 Aerosol-Mediated Cystic Fibrosis Transmembrane Regulator Gene Transfer to the Lungs of Patients with Cystic Fibrosis: A Multicenter, Double-Blind, Placebo-Controlled Trial","volume":"125","author":"Moss","year":"2004","journal-title":"Chest"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1089\/104303401753153956","article-title":"A Phase I Study of Aerosolized Administration of tgAAVCF to Cystic Fibrosis Subjects with Mild Lung Disease","volume":"12","author":"Aitken","year":"2001","journal-title":"Hum. Gene Ther."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Chu, W.S., and Ng, J. (2021). Immunomodulation in Administration of rAAV: Preclinical and Clinical Adjuvant Pharmacotherapies. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.658038"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1517\/17425247.2014.871258","article-title":"The Potential of Adeno-Associated Viral Vectors for Gene Delivery to Muscle Tissue","volume":"11","author":"Wang","year":"2014","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_88","first-page":"683","article-title":"Biodistribution Analysis of Adeno-Associated Viral Vectors of Serotypes 9 and Rh.10 Encoding Arylsulfatase A Following Prior Immunization with Serotype 9 in Pigs","volume":"166","author":"Mullagulova","year":"2024","journal-title":"Acad. Notes Kazan Univ."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1186\/s12967-024-05661-2","article-title":"Designing and Optimizing AAV-Mediated Gene Therapy for Neurodegenerative Diseases: From Bench to Bedside","volume":"22","author":"Xu","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Li, W., Sun, J., Feng, S.L., Wang, F., Miao, M.Z., Wu, E.Y., Wallet, S., Loeser, R., and Li, C. (2023). Intra-Articular Delivery of AAV Vectors Encoding PD-L1 Attenuates Joint Inflammation and Tissue Damage in a Mouse Model of Rheumatoid Arthritis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1116084"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Upadhyay, A., Drag, S., Singh, P., Rajanala, K., and Arumugham, R. (2025). Preclinical Biodistribution and Toxicology Assessment of an AAV5-Based Subretinal Modifier Gene Therapy for Retinitis Pigmentosa. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1679619"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s40259-023-00585-7","article-title":"Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer","volume":"37","author":"Arjomandnejad","year":"2023","journal-title":"BioDrugs"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.omtm.2022.01.011","article-title":"Systemic and Local Immune Responses to Intraocular AAV Vector Administration in Non-Human Primates","volume":"24","author":"Ail","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"100050","DOI":"10.1016\/j.xops.2021.100050","article-title":"An Optimized Treatment Protocol for Subretinal Injections Limits Intravitreal Vector Distribution","volume":"1","author":"Reichel","year":"2021","journal-title":"Ophthalmol. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1016\/j.ymthe.2025.04.045","article-title":"Current Clinical Applications of AAV-Mediated Gene Therapy","volume":"33","author":"Byrne","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Parajuli, S., Gallagher, T., and Flotte, T.R. (2026). Immune Toxicities in AAV Gene Therapy: Overview for Clinicians. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27073196"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"101273","DOI":"10.1016\/j.omtm.2024.101273","article-title":"Global Seroprevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes Used for Human Gene Therapies","volume":"32","author":"Chhabra","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1016\/j.ymthe.2024.05.033","article-title":"Clinical Immunogenicity Outcomes from GENEr8-1, a Phase 3 Study of Valoctocogene Roxaparvovec, an AAV5-Vectored Gene Therapy for Hemophilia A","volume":"32","author":"Long","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1177\/01926233241298892","article-title":"Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors","volume":"52","author":"Assaf","year":"2024","journal-title":"Toxicol. Pathol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.omtm.2022.01.013","article-title":"Characterization of AAV-Mediated Dorsal Root Ganglionopathy","volume":"24","author":"Buss","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1016\/j.neuron.2022.05.003","article-title":"Engineered AAVs for Non-Invasive Gene Delivery to Rodent and Non-Human Primate Nervous Systems","volume":"110","author":"Chen","year":"2022","journal-title":"Neuron"},{"key":"ref_102","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_103","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41434-025-00514-z","article-title":"Incomplete Elimination of Viral Genomes Is Associated with Chronic Inflammation in Nonhuman Primate Livers after AAV-Mediated Gene Transfer","volume":"32","author":"Pichard","year":"2025","journal-title":"Gene Ther."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Artemyev, V., Gubaeva, A., Paremskaia, A.I., Dzhioeva, A.A., Deviatkin, A., Feoktistova, S.G., Mityaeva, O., and Volchkov, P.Y. (2024). Synthetic Promoters in Gene Therapy: Design Approaches, Features and Applications. Cells, 13.","DOI":"10.3390\/cells13231963"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"15055","DOI":"10.1038\/mtm.2015.55","article-title":"AAV9-Mediated Central Nervous System-Targeted Gene Delivery via Cisterna Magna Route in Mice","volume":"3","author":"Lukashchuk","year":"2016","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s10020-023-00680-z","article-title":"Improved Intravenous Lentiviral Gene Therapy Based on Endothelial-Specific Promoter-Driven Factor VIII Expression for Hemophilia A","volume":"29","author":"Gong","year":"2023","journal-title":"Mol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Monahan, P.E., N\u00e9grier, C., Tarantino, M., Valentino, L.A., and Mingozzi, F. (2021). Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia. J. Clin. Med., 10.","DOI":"10.3390\/jcm10112471"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/jvh.13919","article-title":"Hepatitis after Gene Therapy, What Are the Possible Causes?","volume":"31","author":"Maina","year":"2024","journal-title":"J. Viral Hepat."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1038\/s41467-025-57382-9","article-title":"Impact of Liver Fibrosis on AAV-Mediated Gene Transfer to Mouse Hepatocytes","volume":"16","author":"Ferriero","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1038\/s41587-024-02523-6","article-title":"AAV Capsid Prioritization in Normal and Steatotic Human Livers Maintained by Machine Perfusion","volume":"43","author":"Kim","year":"2025","journal-title":"Nat. Biotechnol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.1182\/bloodadvances.2024013750","article-title":"Liver-Related Aspects of Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A: Expert Guidance for Clinical Practice","volume":"8","author":"Cardinale","year":"2024","journal-title":"Blood Adv."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Ertl, H.C.J. (2021). T Cell-Mediated Immune Responses to AAV and AAV Vectors. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.666666"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"101551","DOI":"10.1016\/j.omtm.2025.101551","article-title":"Innate Immune Response to AAV-Based Gene Therapy Vectors: Mechanisms of Complement Activation and Cytokine Release","volume":"33","author":"Xicluna","year":"2025","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Smith, C.J., Ross, N., Kamal, A., Kim, K.Y., Kropf, E., Deschatelets, P., Francois, C., Quinn, W.J., Singh, I., and Majowicz, A. (2022). Pre-Existing Humoral Immunity and Complement Pathway Contribute to Immunogenicity of Adeno-Associated Virus (AAV) Vector in Human Blood. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.999021"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1056\/NEJMoa2005056","article-title":"SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS","volume":"383","author":"Mueller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/jpn3.12326","article-title":"Adeno-Associated Viral Vector Gene Therapy: Challenges for the Paediatric Hepatologist","volume":"79","author":"Jagadisan","year":"2024","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Delire, B., De Martin, E., Meunier, L., Larrey, D., and Horsmans, Y. (2021). Immunotherapy and Gene Therapy: New Challenges in the Diagnosis and Management of Drug-Induced Liver Injury. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.786174"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e209888","DOI":"10.1212\/WNL.0000000000209888","article-title":"Eculizumab Use in Neuromyelitis Optica Spectrum Disorders: Routine Clinical Care Data From a European Cohort","volume":"103","author":"Ringelstein","year":"2024","journal-title":"Neurology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"4266","DOI":"10.1182\/bloodadvances.2021006419","article-title":"Fatal Thrombotic Microangiopathy Case Following Adeno-Associated Viral SMN Gene Therapy","volume":"6","author":"Guillou","year":"2022","journal-title":"Blood Adv."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Rapti, K., and Grimm, D. (2021). Adeno-Associated Viruses (AAV) and Host Immunity\u2014A Race Between the Hare and the Hedgehog. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.753467"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.nmd.2023.09.008","article-title":"261st ENMC International Workshop: Management of Safety Issues Arising Following AAV Gene Therapy. 17th\u201319th June 2022, Hoofddorp, The Netherlands","volume":"33","author":"Servais","year":"2023","journal-title":"Neuromuscul. Disord."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1056\/NEJMoa2307798","article-title":"Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne\u2019s Muscular Dystrophy","volume":"389","author":"Lek","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_123","unstructured":"Uniqure BV (2026, March 26). uniQure Announces Updated Preliminary AMT-191 Phase I\/IIa Data Showing Sustained Increases in \u03b1-Gal A Enzyme Activity in Patients with Fabry Disease. Available online: https:\/\/uniqure.gcs-web.com\/news-releases\/news-release-details\/uniqure-announces-updated-preliminary-amt-191-phase-iiia-data."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/S1474-4422(23)00313-7","article-title":"Safety and Efficacy of Gene Replacement Therapy for X-Linked Myotubular Myopathy (ASPIRO): A Multinational, Open-Label, Dose-Escalation Trial","volume":"22","author":"Shieh","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1056\/NEJMoa1108046","article-title":"Adenovirus-Associated Virus Vector-Mediated Gene Transfer in Hemophilia B","volume":"365","author":"Nathwani","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1007\/s40264-021-01107-6","article-title":"Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy","volume":"44","author":"Day","year":"2021","journal-title":"Drug Saf."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mce.2010.04.005","article-title":"The Anti-Inflammatory and Immunosuppressive Effects of Glucocorticoids, Recent Developments and Mechanistic Insights","volume":"335","author":"Coutinho","year":"2011","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"183","DOI":"10.5500\/wjt.v6.i1.183","article-title":"Immunosuppressive Potency of Mechanistic Target of Rapamycin Inhibitors in Solid-Organ Transplantation","volume":"6","author":"Pons","year":"2016","journal-title":"World J. Transplant."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1177\/096120330501400102","article-title":"Mechanisms of Action of Mycophenolate Mofetil","volume":"14","author":"Allison","year":"2005","journal-title":"Lupus"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/JLB.5MIR0420-055R","article-title":"Roles of IL-2 in Bridging Adaptive and Innate Immunity, and as a Tool for Cellular Immunotherapy","volume":"108","author":"Bendickova","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1097\/00001813-200211002-00002","article-title":"Mechanism of Action of Rituximab","volume":"13","author":"Cerny","year":"2002","journal-title":"Anticancer. Drugs"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Chandler, L.C., Yusuf, I.H., McClements, M.E., Barnard, A.R., MacLaren, R.E., and Xue, K. (2020). Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144972"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"e173510","DOI":"10.1172\/JCI173510","article-title":"Thrombotic Microangiopathy Following Systemic AAV Administration Is Dependent on Anti-Capsid Antibodies","volume":"134","author":"Salabarria","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1089\/hum.2022.138","article-title":"Immune Responses and Immunosuppressive Strategies for Adeno-Associated Virus-Based Gene Therapy for Treatment of Central Nervous System Disorders: Current Knowledge and Approaches","volume":"33","author":"Prasad","year":"2022","journal-title":"Hum. Gene Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1111\/ctr.12361","article-title":"The Incidence, Management, and Evolution of Rapamycin-Related Side Effects in Kidney Transplant Recipients","volume":"28","author":"Verhave","year":"2014","journal-title":"Clin. Transplant."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e948698","DOI":"10.12659\/AJCR.948698","article-title":"Adverse Dermatological Reaction to Mycophenolate Mofetil in a Patient with Systemic Lupus Erythematosus: A Case Report","volume":"26","author":"Cao","year":"2025","journal-title":"Am. J. Case Rep."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1016\/j.transproceed.2019.08.039","article-title":"Inhibition of T Helper Cell Differentiation by Tacrolimus or Sirolimus Results in Reduced B-Cell Activation: Effects on T Follicular Helper Cells","volume":"51","author":"Kraaijeveld","year":"2019","journal-title":"Transplant. Proc."},{"key":"ref_138","unstructured":"(2026, March 26). Drugs@FDA: FDA-Approved Drugs, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm?event=overview.process&ApplNo=050709."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/cc11304","article-title":"Clinical Review: Serious Adverse Events Associated with the Use of Rituximab\u2014A Critical Care Perspective","volume":"16","author":"Kasi","year":"2012","journal-title":"Crit. Care"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/nbt1344","article-title":"Discovery and Development of the Complement Inhibitor Eculizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria","volume":"25","author":"Rother","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41584-020-0372-x","article-title":"Mechanisms of Action of Hydroxychloroquine and Chloroquine: Implications for Rheumatology","volume":"16","author":"Schrezenmeier","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1172\/JCI68205","article-title":"CpG-Depleted Adeno-Associated Virus Vectors Evade Immune Detection","volume":"123","author":"Faust","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41434-021-00296-0","article-title":"Rational Engineering of a Functional CpG-Free ITR for AAV Gene Therapy","volume":"29","author":"Pan","year":"2022","journal-title":"Gene Ther."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1089\/jir.2014.0034","article-title":"dsRNA-Activation of TLR3 and RLR Signaling: Gene Induction-Dependent and Independent Effects","volume":"34","author":"Chattopadhyay","year":"2014","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"e143780, 143780","DOI":"10.1172\/JCI143780","article-title":"Overcoming Innate Immune Barriers That Impede AAV Gene Therapy Vectors","volume":"131","author":"Muhuri","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"111549","DOI":"10.1016\/j.mad.2021.111549","article-title":"Applications of Adeno-Associated Virus Vector-Mediated Gene Delivery for Neurodegenerative Diseases and Psychiatric Diseases: Progress, Advances, and Challenges","volume":"199","author":"Abulimiti","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/978-1-61779-370-7_6","article-title":"AAV-Mediated Liver-Directed Gene Therapy","volume":"807","author":"Sands","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/mt.2014.235","article-title":"Intrinsic Transgene Immunogenicity Gears CD8+ T-Cell Priming after rAAV-Mediated Muscle Gene Transfer","volume":"23","author":"Carpentier","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"12083","DOI":"10.1128\/JVI.05375-11","article-title":"Continuous CD8+ T-Cell Priming by Dendritic Cell Cross-Presentation of Persistent Antigen Following Adeno-Associated Virus-Mediated Gene Delivery","volume":"85","author":"Xu","year":"2011","journal-title":"J. Virol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1089\/hum.2021.124","article-title":"Chemical Modifications of the Capsid for Redirecting and Improving the Efficacy of Adeno-Associated Virus Vectors","volume":"32","author":"Lam","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"e13339","DOI":"10.1111\/cpr.13339","article-title":"Rational Engineering of Adeno-Associated Virus Capsid Enhances Human Hepatocyte Tropism and Reduces Immunogenicity","volume":"55","author":"Han","year":"2022","journal-title":"Cell Prolif."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1089\/hum.2022.170","article-title":"Redosing Adeno-Associated Virus Gene Therapy to the Central Nervous System","volume":"33","author":"McElroy","year":"2022","journal-title":"Hum. Gene Ther."},{"key":"ref_153","first-page":"1276","article-title":"A Systematic Review of Adeno-Associated Virus Gene Therapies in Neurology: The Need for Consistent Safety Monitoring of a Promising Treatment","volume":"93","author":"Horton","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Daci, R., and Flotte, T.R. (2024). Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021050"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s00281-022-00964-2","article-title":"Tissue-Resident Immunity in the Lung: A First-Line Defense at the Environmental Interface","volume":"44","author":"Zazara","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.omtm.2023.02.015","article-title":"Immunosuppression Reduces rAAV2.5T Neutralizing Antibodies That Limit Efficacy Following Repeat Dosing to Ferret Lungs","volume":"29","author":"Tang","year":"2023","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"101244","DOI":"10.1016\/j.omtm.2024.101244","article-title":"Durable Transgene Expression and Efficient Re-Administration after rAAV2.5T-Mediated fCFTR\u0394R Gene Delivery to Adult Ferret Lungs","volume":"32","author":"Tang","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.ymthe.2003.08.015","article-title":"Successful Transgene Expression with Serial Doses of Aerosolized rAAV2 Vectors in Rhesus Macaques","volume":"8","author":"Fischer","year":"2003","journal-title":"Mol. Ther."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0140-6736(16)30371-3","article-title":"Safety and Durability of Effect of Contralateral-Eye Administration of AAV2 Gene Therapy in Patients with Childhood-Onset Blindness Caused by RPE65 Mutations: A Follow-on Phase 1 Trial","volume":"388","author":"Bennett","year":"2016","journal-title":"Lancet"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"591","DOI":"10.47102\/annals-acadmedsg.V37N7p591","article-title":"Effects on the Contralateral Eye after Intravitreal Bevacizumab and Ranibizumab Injections: A Case Report","volume":"37","author":"Wu","year":"2008","journal-title":"Ann. Acad. Med. Singap."},{"key":"ref_161","first-page":"8561895","article-title":"Therapeutic Effect of Anti-VEGF for Age-Related Macular Degeneration in the Untreated Fellow Eye","volume":"2018","author":"Isildak","year":"2018","journal-title":"Case Rep. Ophthalmol. Med."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"101520","DOI":"10.1016\/j.omtm.2025.101520","article-title":"Nonclinical Strategies and Considerations to Enable the Redosing of Gene Therapies","volume":"33","author":"Moffit","year":"2025","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"e2824","DOI":"10.1002\/jmr.2824","article-title":"Combinatorial Screening of Polymer Nanoparticles for Their Ability to Recognize Epitopes of AAV-Neutralizing Antibodies","volume":"33","author":"Piletska","year":"2020","journal-title":"J. Mol. Recognit."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/jgm.1161","article-title":"Coating of Adeno-Associated Virus with Reactive Polymers Can Ablate Virus Tropism, Enable Retargeting and Provide Resistance to Neutralising Antisera","volume":"10","author":"Carlisle","year":"2008","journal-title":"J. Gene Med."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1089\/hum.2014.082","article-title":"Extracellular Vesicles as Enhancers of Virus Vector-Mediated Gene Delivery","volume":"25","author":"Fitzpatrick","year":"2014","journal-title":"Hum. Gene Ther."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"194ra92","DOI":"10.1126\/scitranslmed.3005795","article-title":"Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys","volume":"5","author":"Mingozzi","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1089\/hum.2009.157","article-title":"Adeno-Associated Virus-Mediated Correction of a Canine Model of Glycogen Storage Disease Type Ia","volume":"21","author":"Weinstein","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/gt.2017.75","article-title":"Repeated AAV-Mediated Gene Transfer by Serotype Switching Enables Long-Lasting Therapeutic Levels of hUgt1a1 Enzyme in a Mouse Model of Crigler-Najjar Syndrome Type I","volume":"24","author":"Bortolussi","year":"2017","journal-title":"Gene Ther."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41598-020-57893-z","article-title":"Capsid-Specific Removal of Circulating Antibodies to Adeno-Associated Virus Vectors","volume":"10","author":"Bertin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/mt.2013.244","article-title":"Plasmapheresis Eliminates the Negative Impact of AAV Antibodies on Microdystrophin Gene Expression Following Vascular Delivery","volume":"22","author":"Chicoine","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"101195","DOI":"10.1016\/j.omtm.2024.101195","article-title":"Use of Plasmapheresis to Lower Anti-AAV Antibodies in Nonhuman Primates with Pre-Existing Immunity to AAVrh74","volume":"32","author":"Potter","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.semnephrol.2017.05.020","article-title":"Immunoadsorption in Autoimmune Diseases Affecting the Kidney","volume":"37","author":"Stummvoll","year":"2017","journal-title":"Semin. Nephrol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1056\/NEJMoa1612567","article-title":"IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation","volume":"377","author":"Jordan","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/s41591-020-0911-7","article-title":"IgG-Cleaving Endopeptidase Enables in Vivo Gene Therapy in the Presence of Anti-AAV Neutralizing Antibodies","volume":"26","author":"Leborgne","year":"2020","journal-title":"Nat. Med."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41434-025-00512-1","article-title":"Safety, Efficacy, and Immunogenicity of a Novel IgG Degrading Enzyme (KJ103): Results from Two Randomised, Blinded, Phase 1 Clinical Trials","volume":"32","author":"Cao","year":"2025","journal-title":"Gene Ther."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s42826-024-00195-6","article-title":"A Review of Animal Models Utilized in Preclinical Studies of Approved Gene Therapy Products: Trends and Insights","volume":"40","author":"Soufizadeh","year":"2024","journal-title":"Lab. Anim. Res."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.theriogenology.2007.09.030","article-title":"Are Animal Models as Good as We Think?","volume":"69","author":"Wall","year":"2008","journal-title":"Theriogenology"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1126\/science.283.5398.88","article-title":"Regulated Delivery of Therapeutic Proteins after in Vivo Somatic Cell Gene Transfer","volume":"283","author":"Ye","year":"1999","journal-title":"Science"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"a003566","DOI":"10.1101\/cshperspect.a003566","article-title":"Riboswitches and the RNA World","volume":"4","author":"Breaker","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41587-019-0357-y","article-title":"A Reversible RNA On-Switch That Controls Gene Expression of AAV-Delivered Therapeutics in Vivo","volume":"38","author":"Zhong","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"e18858","DOI":"10.7554\/eLife.18858","article-title":"Rational Design of Aptazyme Riboswitches for Efficient Control of Gene Expression in Mammalian Cells","volume":"5","author":"Zhong","year":"2016","journal-title":"eLife"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1038\/s41587-023-01989-0","article-title":"Control of Mammalian Gene Expression by Modulation of polyA Signal Cleavage at 5\u2032 UTR","volume":"42","author":"Luo","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"e29305","DOI":"10.1002\/jmv.29305","article-title":"Infusion Reactions to Adeno-Associated Virus (AAV)-Based Gene Therapy: Mechanisms, Diagnostics, Treatment and Review of the Literature","volume":"95","author":"Notarte","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_184","unstructured":"(2026, March 26). These Highlights Do Not Include All the Information Needed to Use ZOLGENSMA Safely and Effectively. See Full Prescribing Information for ZOLGENSMA. ZOLGENSMA\u00ae (Onasemnogene Abeparvovec-Xioi) Suspension, for Intravenous Infusion. Initial U.S. Approval: 2019, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=68cd4f06-70e1-40d8-bedb-609ec0afa471."},{"key":"ref_185","unstructured":"(2026, March 26). These Highlights Do Not Include All the Information Needed to Use LUXTURNA Safely and Effectively. See Full Prescribing Information for LUXTURNA.LUXTURNA (Voretigene Neparvovec-Rzyl) Intraocular Suspension for Subretinal Injection. Initial U.S. Approval: 2017, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=08313a24-e7ce-457a-bb3f-161bc45517ee."},{"key":"ref_186","unstructured":"(2026, March 26). These Highlights Do Not Include All the Information Needed to Use HEMGENIX Safely and Effectively. See Full Prescribing Information for HEMGENIX. HEMGENIX (Etranacogene Dezaparvovec-Drlb) Suspension, for Intravenous Infusion. Initial U.S. Approval: 2022, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=35b2db65-4c6c-4173-ab56-b2bca69193bd&type=display."},{"key":"ref_187","unstructured":"(2026, March 26). These Highlights Do Not Include All the Information Needed to Use ROCTAVIAN Safely and Effectively. See Full Prescribing Information for ROCTAVIAN. ROCTAVIAN (Valoctocogene Roxaparvovec-Rvox) Suspension for Intravenous Infusion. Initial U.S. Approval: 2023, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=0dcf7185-8e1c-456a-9d4e-7cc316400118."},{"key":"ref_188","unstructured":"(2026, March 26). These Highlights Do Not Include All the Information Needed to Use ELEVIDYS\u00ae Safely and Effectively. See Full Prescribing Information for ELEVIDYS. ELEVIDYS (Delandistrogene Moxeparvovec-Rokl) Suspension, for Intravenous Infusion. Initial U.S. Approval: 2023, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=3525abcd-fbd2-46c5-9706-cffdf2e8a361&type=display."},{"key":"ref_189","unstructured":"(2026, March 26). These Highlights Do Not Include All the Information Needed to Use KEBILIDI Safely and Effectively. See Full Prescribing Information for KEBILIDI. KEBILIDI (Eladocagene Exuparvovec-Tneq) Suspension, for Intraputaminal Infusion. Initial U.S. Approval: 2024, Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/fda\/fdaDrugXsl.cfm?setid=9d6a6401-c6b5-4f29-af11-67707d249482&type=display."},{"key":"ref_190","unstructured":"European Medicines Agency (EMA) (2026, March 26). Upstaza. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/upstaza."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s13075-022-02886-8","article-title":"Abatacept Downregulates Fc\u03b3 Receptor I on Circulating Monocytes: A Potential Therapeutic Mechanism in Patients with Rheumatoid Arthritis","volume":"24","author":"Fukue","year":"2022","journal-title":"Arthritis Res. Ther."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"e2404661121","DOI":"10.1073\/pnas.2404661121","article-title":"Post-Immunotherapy CTLA-4 Ig Treatment Improves Antitumor Efficacy","volume":"121","author":"Mok","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1111\/jth.14757","article-title":"Blockade of the Costimulatory CD28-B7 Family Signal Axis Enables Repeated Application of AAV8 Gene Vectors","volume":"18","author":"Frentsch","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"4098","DOI":"10.1038\/s41467-018-06621-3","article-title":"Antigen-Selective Modulation of AAV Immunogenicity with Tolerogenic Rapamycin Nanoparticles Enables Successful Vector Re-Administration","volume":"9","author":"Meliani","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.omtm.2021.06.015","article-title":"ImmTOR Nanoparticles Enhance AAV Transgene Expression after Initial and Repeat Dosing in a Mouse Model of Methylmalonic Acidemia","volume":"22","author":"Ilyinskii","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"8906","DOI":"10.1038\/s41467-025-63970-6","article-title":"Transient Rapamycin Treatment Avoids Unwanted Host Immune Responses toward AAV-Delivered Anti-HIV Antibodies","volume":"16","author":"Fuchs","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"eabd0321","DOI":"10.1126\/sciadv.abd0321","article-title":"Enhancement of Liver-Directed Transgene Expression at Initial and Repeat Doses of AAV Vectors Admixed with ImmTOR Nanoparticles","volume":"7","author":"Ilyinskii","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1089\/hum.2023.194","article-title":"Complement System Response to Adeno-Associated Virus Vector Gene Therapy","volume":"35","author":"Kropf","year":"2024","journal-title":"Hum. Gene Ther."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1097\/TP.0000000000004689","article-title":"Imlifidase Desensitization in HLA-Incompatible Kidney Transplantation: Finding the Sweet Spot","volume":"108","author":"Roelen","year":"2024","journal-title":"Transplantation"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1097\/TP.0000000000003496","article-title":"Imlifidase Desensitization in Crossmatch-Positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes)","volume":"105","author":"Jordan","year":"2021","journal-title":"Transplantation"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"e139881, 139881","DOI":"10.1172\/jci.insight.139881","article-title":"Rescuing AAV Gene Transfer from Neutralizing Antibodies with an IgG-Degrading Enzyme","volume":"5","author":"Elmore","year":"2020","journal-title":"JCI Insight"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1016\/j.ymthe.2024.05.004","article-title":"Engineered IgM and IgG Cleaving Enzymes for Mitigating Antibody Neutralization and Complement Activation in AAV Gene Transfer","volume":"32","author":"Smith","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ymthe.2005.03.018","article-title":"Local Administration of an Adeno-Associated Viral Vector Expressing IL-10 Reduces Monocyte Infiltration and Subsequent Photoreceptor Damage during Experimental Autoimmune Uveitis","volume":"12","author":"Broderick","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"103728","DOI":"10.1016\/j.cellimm.2017.12.002","article-title":"Liver Induced Transgene Tolerance with AAV Vectors","volume":"342","author":"Keeler","year":"2019","journal-title":"Cell Immunol."},{"key":"ref_205","doi-asserted-by":"crossref","unstructured":"Samelson-Jones, B.J., and Arruda, V.R. (2020). Translational Potential of Immune Tolerance Induction by AAV Liver-Directed Factor VIII Gene Therapy for Hemophilia A. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00618"},{"key":"ref_206","doi-asserted-by":"crossref","unstructured":"Patel, S.R., Lundgren, T.S., Spencer, H.T., and Doering, C.B. (2020). The Immune Response to the fVIII Gene Therapy in Preclinical Models. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00494"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-1-0716-2707-5_18","article-title":"Selective Anti-AAV Antibody Depletion by Hemapheresis and Immunoadsorption","volume":"2573","author":"Orlowski","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1038\/mt.2011.108","article-title":"A 10 Patient Case Report on the Impact of Plasmapheresis upon Neutralizing Factors against Adeno-Associated Virus (AAV) Types 1, 2, 6, and 8","volume":"19","author":"Monteilhet","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1111\/ajt.16828","article-title":"Imlifidase for the Treatment of Anti-HLA Antibody-Mediated Processes in Kidney Transplantation","volume":"22","author":"Huang","year":"2022","journal-title":"Am. J. Transplant."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1038\/mt.2015.179","article-title":"Comparative Study of Liver Gene Transfer With AAV Vectors Based on Natural and Engineered AAV Capsids","volume":"23","author":"Wang","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/mtm.2013.9","article-title":"Empty Virions in AAV8 Vector Preparations Reduce Transduction Efficiency and May Cause Total Viral Particle Dose-Limiting Side-Effects","volume":"1","author":"Gao","year":"2014","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"101407","DOI":"10.1016\/j.omtm.2025.101407","article-title":"Probing Aspects of Extracellular Vesicle Associated AAV Allows Increased Vector Yield and Insight into Its Transduction and Immune-Evasive Properties","volume":"33","author":"Cheng","year":"2025","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1182\/bloodadvances.2017010181","article-title":"Enhanced Liver Gene Transfer and Evasion of Preexisting Humoral Immunity with Exosome-Enveloped AAV Vectors","volume":"1","author":"Meliani","year":"2017","journal-title":"Blood Adv."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41593-021-00969-4","article-title":"AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting after Intravenous Delivery in Mouse and Marmoset","volume":"25","author":"Goertsen","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"e20240031","DOI":"10.1002\/INMD.20240031","article-title":"Adeno-associated Virus Vectors for Gene Therapy\u2014Focusing on Melanoma","volume":"2","author":"Wang","year":"2024","journal-title":"Interdiscip. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:25:47Z","timestamp":1780028747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":215,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114818"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114818","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}