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Editor noteEditor's note Open Access | 10.1172/JCI177078

Improving the safety of systemic viral gene therapy

Elizabeth M. McNally, Editor in Chief

Find articles by McNally, E. in: PubMed | Google Scholar

Published January 2, 2024 - More info

Published in Volume 134, Issue 1 on January 2, 2024
J Clin Invest. 2024;134(1):e177078. https://doi.org/10.1172/JCI177078.
© 2024 McNally et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 2, 2024 - Version history
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Related article:

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies
Stephanie M. Salabarria, … , Jonathan D. Schwartz, Barry J. Byrne
Stephanie M. Salabarria, … , Jonathan D. Schwartz, Barry J. Byrne
Thrombotic microangiopathy in the setting of adeno-associated virus gene therapy is antibody dependent as part of the classical complement pathway.
Clinical Research and Public Health Genetics Immunology

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies

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Abstract

BACKGROUND Systemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome–like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODS We describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTS Group 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONS This study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.

Authors

Stephanie M. Salabarria, Manuela Corti, Kirsten E. Coleman, Megan B. Wichman, Julie A. Berthy, Precilla D’Souza, Cynthia J. Tifft, Roland W. Herzog, Melissa E. Elder, Lawrence R. Shoemaker, Carmen Leon-Astudillo, Fatemeh Tavakkoli, David H. Kirn, Jonathan D. Schwartz, Barry J. Byrne

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Systemic treatment with adeno-associated virus (AAV) gene replacement therapy has seen gains with FDA approval for onasemnogene abeparvovec (trade name Zolgensma) in 2019 to treat spinal muscular atrophy (SMA) and approval for delandistrogne (trade name Elevidys) in 2023 to treat Duchenne muscular dystrophy (DMD) (1). Additional ongoing clinical trials are evaluating the efficacy and safety of systemic AAV gene therapy for multiple rare genetic conditions. Experience in systemic AAV dosing is providing a wealth of information about side effects from gene therapy, especially the immune response to AAV capsid and the expressed products; however, much of the information gleaned remains uncurated and dispersed among institutions. In this issue of the JCI, Salabarria and colleagues report on their study with alternative immunosuppression strategies in human patients receiving approved or experimental AAV9 gene therapy (2). Notably, the authors cataloged data from 38 children who received several different gene therapy protocols and collated the information at a single center (2).

Systemic AAV gene therapy requires substantial doses, typically 1 × 1013 to 2 × 1014 vector genomes per kg, which trigger both innate and humoral responses (3). Thrombotic microangiopathy (TMA), a potentially life-threatening condition, can occur relatively early after dosing and is characterized by thrombocytopenia, hemolytic anemia, and end-organ damage to the heart, lungs, kidneys, and other organs. In a nonrandomized series, Salabarria et al. (2) evaluated patients receiving AAV9 for multiple conditions, including SMA, GM1 gangliosidosis, DMD, and Danon disease. The patients were divided into two groups; one group received only corticosteroids, while the second group additionally received rituximab and sirolimus. After AAV dosing, Group 1 patients showed a spike in anti-capsid IgG and IgM antibodies, complement activation, and a reduction in platelets. In contrast, the Group 2 patients did not have the acute rise in anti-capsid IgG and IgM antibodies nor did they display the same degree of complement activation or platelet drop. The authors conclude that a conditioning regimen with rituximab and sirolimus can reduce the likelihood of TMA. By the nature of the study design, the groups were unequal in age and the specific gene therapy being delivered, so additional studies are needed to evaluate this conditioning regimen and others.

Lek et al. recently reported the death of a young adult with DMD who received AAV gene therapy to drive dystrophin upregulation using an inactivated Cas9-VP64 domain (4). Despite receiving rituximab and sirolimus, the patient died with cardiac and pulmonary failure approximately one week after receiving gene therapy. The ante- and postmortem studies documented thrombocytopenia, some complement activation, and a preexisting severe cardiomyopathy. The timing of death and molecular studies indicated immunity to the AAV capsid itself, rather than the gene editing machinery, as no expression of the gene editing machinery was detected.

The unique diversity of the human immune system and its reaction to high-dose AAV is poorly modeled in preclinical animal studies, so it is only through human AAV gene therapy trials that more can be learned. An array of immunomodulatory agents is available to manage outcomes to viral gene therapy, and immunomodulation regimens are often not precisely stipulated by the clinical trial design or the package label. Immunomodulatory management of viral gene therapy is not unlike organ transplant management. For organ transplantation, registries have been invaluable to record management and outcomes. Indeed, a recent report of immune responses in three different AAV gene therapy trials for DMD was able to identify a target antigen driving an immune response only because these trials shared common investigators (5). The work by Salabarria et al. (2) reminds us that registries for cataloging immune management and outcomes can improve safety and efficacy of AAV for all and should be considered for gene therapy.

Footnotes

Conflict of interest: EMM has been or is a consultant to Amgen, AstraZeneca, Avidity Biosciences, Cytokinetics, 4D Molecular Therapeutics, Pfizer, and Tenaya Therapeutics. EMM is also a founder of Ikaika Therapeutics.

Copyright: © 2024, McNally et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2024;134(1):e177078. https://doi.org/10.1172/JCI177078.

See the related article at Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

References
  1. FDA. Approved Cellular and Gene Therapy Producsts. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products Updated June 30, 2023. Accessed November 6, 2023.
  2. Salabarria SM, et al. Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies. J Clin Invest. 2024;134(1):e173510.
    View this article via: JCI PubMed CrossRef Google Scholar
  3. Lek A, et al. Meeting report: 2022 Muscular Dystrophy Association summit on ‘safety and challenges in gene transfer therapy’. J Neuromuscul Dis. 2023;10(3):327–336.
    View this article via: CrossRef PubMed Google Scholar
  4. Lek A, et al. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med. 2023;389(13):1203–1210.
    View this article via: CrossRef PubMed Google Scholar
  5. Bönnemann CG, et al. Dystrophin immunity after gene therapy for Duchenne’s muscular dystrophy. N Engl J Med. 2023;388(24):2294–2296.
    View this article via: CrossRef PubMed Google Scholar
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