Cited by 330Virus-based gene therapy researchHemophilia Treatment and ResearchRNA Interference and Gene Delivery

Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy

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Jiang, Haiyan, Couto, Linda B., Patarroyo-White, Susannah, Liu, Tongyao, Nagy, Dea, Vargas, Joseph A., Zhou, Shangzhen, Scallan, Ciaran D. +5 more·2006·Blood

Abstract

In a clinical study of recombinant adeno-associated virus-2 expressing human factor IX (AAV2-FIX), we detected 2 impediments to long-term gene transfer. First, preexisting anti-AAV neutralizing antibodies (NABs) prevent vector from reaching the target tissue, and second, CD8+ T-cell responses to hepatocyte-cell surface displayed AAV-capsid–terminated FIX expression after several weeks. Because the vector is incapable of synthesizing viral proteins, a short course of immunosuppression, until AAV capsid is cleared from the transduced cells, may mitigate the host T-cell response, allowing long-term expression of FIX. To evaluate coad-ministration of immunosuppression, we studied AAV8 vector infusion in rhesus macaques, natural hosts for AAV8. We administered AAV8-FIX in 16 macaques via the hepatic artery and assessed the effects of (1) preexisting anti-AAV8 NABs, (2) a standard T-cell immunosuppressive regimen, and (3) efficacy and safety of AAV8-FIX. We found that low titers (1:5) of preexisting NABs abrogate transduction, whereas animals with undetectable NABs are safely and effectively transduced by AAV8-FIX. Coadministration of mycophenolate mofetil and tacrolimus with vector does not induce toxicity and does not impair AAV transduction or FIX synthesis. These findings enable a clinical study to assess the effects of immunomodulation on long-term FIX expression in patients with hemophilia B.

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Crossref · 10.1182/blood-2006-04-017913

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  • Transient immunosuppression is not effective at mitigating vector neutralization by pre-existing antibodies.

    “While transient immunosuppression may be a promising approach for reducing cellular immune responses to gene therapy,39–41 it is not effective at mitigating vector neutralization by pre-existing antibodies.”

    From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [40]

    The Results section on preexisting AAV8 neutralizing antibodies reports that antibodies at a titer of 1:5 neutralized the vector and prevented detectable FIX expression in rhesus macaques (page unavailable). The Discussion says the transient anti-T-cell regimen did not reliably block the antibody response to AAV capsid (page unavailable). However, the cited passages do not show a direct test of whether that regimen mitigated neutralization by antibodies already present before treatment. (LLM, conf=0.83)

    Experimental — accuracy not yet measured
  • In nonhuman primates, MMF combined with tacrolimus did not inhibit liver transduction of AAV8.

    “when tested in combination with tacrolimus in NHPs, MMF did not inhibit liver transduction of AAV8 (45).”

    From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [45]

  • Pre-existing neutralizing antibody (NAb) can effectively block rAAV transduction even at low levels (1:5).

    “Pre-existing neutralizing antibody (NAb) can effectively block rAAV transduction even at low levels (1:5) (6).”
  • No difference in AAV8-hFIX transgene expression was observed when administered with tacrolimus in NHP.

    “No difference in AAV8-hFIX transgene expression was observed when administered with tacrolimus in NHP (6), highlighting the difficulties of recapitulating human immune system in mouse models.”

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Authors
Jiang, H., Couto, L. B., Patarroyo-White, S., Liu, T., Nagy, D., Vargas, J. A., Zhou, S., Scallan, C. D., Sommer, J., Vijay, S., Mingozzi, F., High, K. A., & Pierce, G. F.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • From Avigen Inc, Alameda, CA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and Howard Hughes Medical Institute, Children's Hospital of Philadelphia, Philadelphia, PA.
Venue
Blood
Published
2006-11-15
Volume
108
Issue
10
Pages
3321-3328
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
OpenAlex
W2067204822
Cited by
330
References
34
Citations by year
2026: 7 · 2025: 17 · 2024: 17 · 2023: 22 · 2022: 24 · 2021: 21 · 2020: 19 · 2019: 21 · 2018: 16 · 2017: 18 · 2016: 8 · 2015: 25 · 2014: 12 · 2013: 15 · 2012: 24
FWCI
6.07
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Bayer HealthCare
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (U01HL066948, P01HL078810, U01-HL66948)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
adeno-associated virus, AAV8, factor IX, hemophilia B, liver-directed gene transfer, immunosuppression, CD8+ T cell responses, mycophenolate mofetil, tacrolimus, hepatic artery infusion, rhesus monkeys, long-term gene expression, gene therapy
MeSH terms
Dependovirus, Animals, Antibodies, Hemophilia B, Drug Therapy, Combination, Factor IX, Genetic Vectors, Humans, Immunosuppression Therapy, Liver, Macaca mulatta, Male, Mycophenolic Acid, Organ Specificity, Genetic Therapy, Tacrolimus, Gene Transfer Techniques, Mice

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