Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies
Stephanie M Salabarria1, Manuela Corti1, Kirsten E Coleman1
1Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
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.
Insights
Systemic adeno-associated virus (AAV) gene therapy can cause dangerous inflammation. A new study shows that a combination therapy of rituximab, sirolimus, and steroids effectively prevents immune activation and thrombotic microangiopathy (TMA).
Area of Science:
- Immunology
- Gene Therapy
- Toxicology
Background:
- Systemic adeno-associated virus (AAV) administration can cause severe inflammatory reactions.
- These reactions include thrombotic microangiopathy (TMA), kidney injury, myocardial inflammation, and liver toxicity.
Purpose of the Study:
- To investigate immune activation kinetics after systemic AAV9 administration.
- To evaluate two distinct prophylactic immunomodulation regimens for preventing AAV-related adverse events.
Main Methods:
- Studied 38 individuals receiving systemic AAV9 with two regimens: corticosteroids alone (Group 1) or corticosteroids plus rituximab and sirolimus (Group 2).
- Monitored immune markers, including immunoglobulins (IgM, IgG), D-dimer, platelet count, and complement pathway activation (C4, C5b-9, Ba, Bb).
Main Results:
- Group 1 showed rapid increases in IgM and IgG, indicative of TMA, with activation of both classical and alternative complement pathways.
- Group 2 exhibited minimal changes in immunoglobulins and complement activation.
- TMA markers like elevated D-dimer and decreased platelets were observed in Group 1.
Conclusions:
- Thrombotic microangiopathy (TMA) in AAV gene therapy is antibody-dependent, involving the classical complement pathway.
- The alternative complement pathway amplifies TMA development.
- Identified critical interventions for managing immune-mediated events in systemic gene therapy.
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