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However, both variability and durability of transgene expression remain a challenge, limiting treatment predictability. Comparative preclinical and human liver biopsy studies suggest that transcriptional efficiency, rather than vector genome copy number (VCN), is a primary determinant of variability and durability in treatment response. Despite the presence of vector genomes in hepatocytes, transcriptional output varies significantly across species and individuals, indicating that VCN alone is insufficient to predict therapeutic efficacy. This review synthesizes findings from preclinical models (mice, dogs, non-human primates (NHPs), and human hepatocytes) and clinical liver biopsy studies to examine mechanisms influencing AAV gene therapy variability and durability. While vector genome retention is relatively comparable across species, transcriptional efficiency declines in higher species, particularly in NHPs, dogs, and humans. Beyond transcription, vector genome loss, hepatocyte turnover, immune responses, and cellular stress (e.g., endoplasmic reticulum (ER) stress) may contribute to intraindividual declines in transgene expression over time. Recent findings also highlight the role of epigenetic modifications, vector integration patterns, and translational shutdown linked to protein-folding stress in influencing durability. Expression patterns show greater long-term stability with factor IX (FIX) gene therapy compared to factor VIII (FVIII), which often declines more sharply. Distinctions may reflect differences in protein biosynthetic burden and cellular stress responses, particularly for FVIII. Most FIX trials use the highly active Padua variant, enabling lower expression levels with potentially less cellular stress, while the tendency of FVIII to misfold and trigger ER stress may contribute to transcriptional or translational shutdown over time. Integrating insights from preclinical models, human liver biopsies, and ongoing clinical trials, this review refines our understanding of AAV gene therapy variability and durability, ultimately guiding next-generation gene therapies to enhance long-term clinical efficacy.<\/jats:p>","DOI":"10.1177\/20406207251406537","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T04:44:54Z","timestamp":1769748294000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Translational insights from nonclinical studies of AAV gene therapies for hemophilia: mechanisms underpinning variability and durability of gene expression"],"prefix":"10.1177","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-4146","authenticated-orcid":false,"given":"Sylvia","family":"Fong","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Queen\u2019s University, Kingston, ON, K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-8401","authenticated-orcid":false,"given":"Laura L.","family":"Swystun","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Queen\u2019s University, Kingston, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7808-3462","authenticated-orcid":false,"given":"Paul","family":"Batty","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Queen\u2019s University, Kingston, ON, Canada"},{"name":"Department of Haematology, Cancer Institute, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2410-6312","authenticated-orcid":false,"given":"David","family":"Lillicrap","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Queen\u2019s University, Kingston, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/312326a0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/299178a0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/303474a0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.274"},{"key":"e_1_3_4_6_2","unstructured":"The European Association for Haemophilia and Allied Disorders. 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