IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice
Open accessAbstract
Hepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials. Following liver-directed AAV8 gene transfer in the presence of rapamycin, initial FVIII protein expression declines over time in the absence of antibody formation. Surprisingly, loss of FVIII protein production occurs despite persistence of transgene and mRNA, suggesting a translational shutdown rather than a loss of transduced hepatocytes. Some of the animals develop ER stress, which may be linked to hepatic inflammatory cytokine expression. FVIII protein expression is preserved by interleukin-15/interleukin-15 receptor blockade, which suppresses CD8 + T and natural killer cell responses. Interestingly, mice with initial FVIII levels >100% of normal had diminishing expression while still under immune suppression. Taken together, our findings of interanimal variability of the response, and the ability of the immune system to shut down transgene expression without utilizing cytolytic or antibody-mediated mechanisms, illustrate the challenges associated with FVIII gene transfer. Our protocols based upon cytokine blockade should help to maintain efficient FVIII expression.
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Initial priming of CD8+ T cells in the hepatic environment would explain the delayed functionality of the response previously documented in the C57BL/6-OVA model and in hemophilia A mice responding to FVIII.
“Initial priming of CD8+ T cells in the hepatic environment would explain the delayed functionality of the response that we previously documented in both the C57BL/6-OVA model and in hemophilia A mice responding to FVIII.15,37”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [37]
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Self-citationOptimizing liver health before and after gene therapy for hemophilia A
Ragni, M. V., Mead, H., de Jong, Y. P., Kaczmarek, R., Leavitt, A. D., Long, B. R., Nugent, D. J., Sabatino, D. E., Fong, S., von Drygalski, A., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2024013059 · Cited by 19 · see citing works
Chapin, J. C., Román, M. T. Á., Ayash‐Rashkovsky, M., Diogo, D., Kenniston, J. A., López‐Jaime, F. J., Maggiore, C., Mingot‐Castellano, M. E., Rajavel, K. S., Rauch, A., et al. (2024) · Haemophilia · doi:10.1111/hae.15121 · Cited by 13 · see citing works
Muñoz-Melero, M., & Biswas, M. (2024) · Human Gene Therapy · doi:10.1089/hum.2023.227 · Cited by 13 · see citing works
Self-citationRescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer
Laurent, M., Harb, R., Jenny, C., Oustelandt, J., Jimenez, S., Cosette, J., Landini, F., Ferrante, A., Corre, G., Vujić, N., et al. (2025) · Communications Medicine · doi:10.1038/s43856-025-00816-8 · Cited by 13 · see citing works
Potential role for oral tolerance in gene therapy
Butterfield, J. S. S., Li, X., Arisa, S., Kwon, K., Daniell, H., & Herzog, R. W. (2023) · Cellular Immunology · doi:10.1016/j.cellimm.2023.104742 · Cited by 8 · see citing works
Self-citationSynergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver
Jauze, L., Vie, M., Miagoux, Q., Rossiaud, L., Vidal, P., Montalvo-Romeral, V., Saliba, H., Jarrige, M., Polvèche, H., Nozi, J., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.172614 · Cited by 8 · see citing works
Distinct functions and transcriptional signatures in orally induced regulatory T cell populations
Biswas, M., So, K., Bertolini, T. B., Krishnan, P., Rana, J., Muñoz-Melero, M., Syed, F., Kumar, S. R. P., Gao, H., Xuei, X., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1278184 · Cited by 5 · see citing works
Self-citationViral Vector Based Immunotherapy for Peanut Allergy
Gonzalez-Visiedo, M., Herzog, R. W., Muñoz-Melero, M., Blessinger, S. A., Cook‐Mills, J. M., Daniell, H., & Markusic, D. M. (2024) · Viruses · doi:10.3390/v16071125 · Cited by 4 · see citing works
Self-citationLooking to the future of gene therapy for hemophilia A and B
Kaczmarek, R., & Herzog, R. W. (2023) · Expert Review of Hematology · doi:10.1080/17474086.2023.2268279 · Cited by 4 · see citing works
Self-citationFong, S., Swystun, L. L., Batty, P. A., & Lillicrap, D. (2026) · Therapeutic Advances in Hematology · doi:10.1177/20406207251406537 · Cited by 3 · see citing works
Current Status of Clinical Gene Therapy for Hemophilia and Globin Disorders
Winkler, R., Herath, I., Kaczmarek, R., Xiao, W., Herzog, R. W., & Severeid, P. (2026) · Journal of Blood Medicine · doi:10.2147/jbm.s576017 · Cited by 3 · see citing works
Self-citationTuddenham, E. G. D., & Foster, G. R. (2024) · Journal of Viral Hepatitis · doi:10.1111/jvh.13934 · Cited by 3 · see citing works
Accessorizing viral vectors with extracellular vesicles for enhanced performance
Maguire, C. A. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.03.031 · Cited by 3 · see citing works
Artemyev, V., Paremskaia, A. I., Dzhioeva, A. A., Mishina, D., Bogdanov, V. P., Krupinova, J. A., Mazloum, A., Feoktistova, S. G., Mityaeva, O. N., & Volchkov, P. (2025) · Cells · doi:10.3390/cells15010014 · Cited by 2 · see citing works
Hemophilia “A” gene therapy: Lost in translation
VandenDriessche, T., & Chuah, M. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.11.006 · Cited by 2 · see citing works
Puetz, J. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1256919 · Cited by 2 · see citing works
Identification of alterations of immunometabolism associated with Pompe disease
Verdera, H. C., Gargaro, M., Cagin, U., Manni, G., Scalisi, G., Veron, P., Barcelos, E. C. S., Pieroni, B., Mencarelli, G., Ricciuti, D., et al. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06135-y · Cited by 1 · see citing works
An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies
Ogurlu, R., Sanchez, E. B., Hull, J. A., Fergione, S., Yudistyra, V., Webb, G. M., Wu, H. L., Pessoa, C. T., Humkey, M. C., Potter, S. K., et al. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.07.006
Hepatotoxicity in clinical gene therapy for hemophilia A: Cellular stress and the immune system
Herzog, R. W., & Kaczmarek, R. (2026) · Molecular Therapy · doi:10.1016/j.ymthe.2026.09.009
Self-citation
- Authors
- Butterfield, J. S. S., Yamada, K., Bertolini, T. B., Syed, F., Kumar, S. R. P., Li, X., Arisa, S., Piñeros, A. R., Tapia, A., Rogers, C. A., Li, N., Rana, J., Biswas, M., Terhorst, C., Kaufman, R. J., de Jong, Y. P., & Herzog, R. W.
- Affiliations
- University of Florida Health (US)
- Indiana University Indianapolis (US)
- Beth Israel Deaconess Medical Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Herzog, Roland W.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 30
- Issue
- 12
- Pages
- 3552-3569
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC9734025
- OpenAlex
- W4285098511
- Cited by
- 36
- References
- 67
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 9 · 2023: 14 · 2022: 3
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (P30 CA082709)
- National Heart Lung and Blood Institute (R01 HL131093, U54 HL142012, P01HL160472)
- Riley Children's Foundation
- National Institute of Allergy and Infectious Diseases (R01AI51390)
- Lilly Endowment Inc
- Spark Therapeutics
- National Institute of Diabetes and Digestive and Kidney Diseases (T32AI060519, U54 DK106846, 1S10D012270)
- Indiana University
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- hemophilia A, factor VIII, liver-directed gene therapy, rapamycin, endoplasmic reticulum stress, hepatocyte loss, CD8+ T cells, natural killer cells, cytokine inhibition, immune tolerance, X-linked bleeding disorder
- MeSH terms
- Animals, Factor VIII, Interleukin-15, Sirolimus, Mice
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