Barry J. Byrne, Russell J. Butterfield, Perry B. Shieh, Edward C. Smith, Christoph Licht, Michael Binks, Sandra Casinghino, Marielle Delnomdedieu, Kodihalli C. Ravindra, Tara McDonnell, Kelly Ryan, Martin Schulz, Qi Shen, Heliang Shi, Madhu P. Sirivelu, Vishal S. Vaidya, Laurence Whiteley, Daniel I. Levy
{"title":"Complement Activation in a Phase Ib Study of Fordadistrogene Movaparvovec for Duchenne Muscular Dystrophy","authors":"Barry J. Byrne, Russell J. Butterfield, Perry B. Shieh, Edward C. Smith, Christoph Licht, Michael Binks, Sandra Casinghino, Marielle Delnomdedieu, Kodihalli C. Ravindra, Tara McDonnell, Kelly Ryan, Martin Schulz, Qi Shen, Heliang Shi, Madhu P. Sirivelu, Vishal S. Vaidya, Laurence Whiteley, Daniel I. Levy","doi":"10.1016/j.ymthe.2025.06.032","DOIUrl":null,"url":null,"abstract":"Thrombotic microangiopathy (TMA) has been reported as an uncommon but severe adverse effect of recombinant adeno-associated virus (rAAV)-based gene therapy. Here, we describe in detail the occurrences of clinically evident TMA following infusion of the rAAV9-based therapy fordadistrogene movaparvovec (1 or 3 x 10<ce:sup loc=\"post\">14</ce:sup> vg/kg) in 22 participants with Duchenne muscular dystrophy (DMD). Three participants experienced clinical evidence of TMA. Platelet levels rapidly decreased 7-10 days post-infusion, together with C3 and C4 depletion and elevated C5b-9 after ∼7 days. Peak vector blood concentration was observed for 4-7 days, and Type 1 interferon cytokine levels increased within 2-7 days. Each affected participant was hospitalized, received supportive care and anti-complement therapy. Anti-AAV9 IgM and IgG were detected within days post-infusion, and participants with TMA demonstrated a particularly rapid rise of neutralizing antibodies and total antibody to AAV9 in the first 1–2 weeks post-infusion. Limited early time points from other participants were not assessed for complement activation. With appropriate monitoring of early time points following AAV exposure, TMA can be successfully managed. However, these early events should be considered related to the benefit-risk profile when using rAAV-based gene therapy for the treatment of DMD. <ce:inter-ref xlink:href=\"http://ClinicalTrials.gov\" xlink:type=\"simple\">ClinicalTrials.gov</ce:inter-ref> identifier: NCT03362502.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.1000,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.06.032","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Thrombotic microangiopathy (TMA) has been reported as an uncommon but severe adverse effect of recombinant adeno-associated virus (rAAV)-based gene therapy. Here, we describe in detail the occurrences of clinically evident TMA following infusion of the rAAV9-based therapy fordadistrogene movaparvovec (1 or 3 x 1014 vg/kg) in 22 participants with Duchenne muscular dystrophy (DMD). Three participants experienced clinical evidence of TMA. Platelet levels rapidly decreased 7-10 days post-infusion, together with C3 and C4 depletion and elevated C5b-9 after ∼7 days. Peak vector blood concentration was observed for 4-7 days, and Type 1 interferon cytokine levels increased within 2-7 days. Each affected participant was hospitalized, received supportive care and anti-complement therapy. Anti-AAV9 IgM and IgG were detected within days post-infusion, and participants with TMA demonstrated a particularly rapid rise of neutralizing antibodies and total antibody to AAV9 in the first 1–2 weeks post-infusion. Limited early time points from other participants were not assessed for complement activation. With appropriate monitoring of early time points following AAV exposure, TMA can be successfully managed. However, these early events should be considered related to the benefit-risk profile when using rAAV-based gene therapy for the treatment of DMD. ClinicalTrials.gov identifier: NCT03362502.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.