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

Article · Salabarria SM, Corti M, Coleman KE, Wichman MB, Berthy JA, D'Souza P, Tifft CJ, Herzog RW, Elder ME, Shoemaker LR, Leon-Astudillo C, Tavakkoli F, Kirn DH, Schwartz JD, Byrne BJ

- Archive id: doi:10.1172/jci173510
- Published: 2024-01-02
- Venue: The Journal of clinical investigation
- DOI: https://doi.org/10.1172/jci173510
- PMID: 37988172
- PMCID: PMC10760971
- Citations: 116
- Source URL: https://doi.org/10.1172/jci173510
- PDF: https://europepmc.org/articles/PMC10760971/pdf
- Provenance: europepmc

## Abstract

BACKGROUNDSystemic 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.METHODSWe 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.RESULTSGroup 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.CONCLUSIONSThis 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.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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