Complement Activation in a Phase Ib Study of Fordadistrogene Movaparvovec for Duchenne Muscular Dystrophy

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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
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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.
Fordadistrogene Movaparvovec治疗杜氏肌营养不良的补体激活Ib期研究
血栓性微血管病(TMA)是重组腺相关病毒(rAAV)基因治疗中一种罕见但严重的不良反应。在这里,我们详细描述了22名杜氏肌营养不良(DMD)患者在输注以raav9为基础的治疗(1或3 x 1014vg /kg)后临床明显的TMA的发生。三名参与者经历了TMA的临床证据。血小板水平在输注后7-10天迅速下降,同时C3和C4耗竭,7天后C5b-9升高。载体血药浓度峰值持续4 ~ 7 d, 1型干扰素细胞因子水平在2 ~ 7 d内升高。每位受影响的参与者都住院治疗,接受支持性护理和抗补体治疗。在注射后几天内检测抗AAV9 IgM和IgG, TMA参与者在注射后的前1-2周内表现出对AAV9的中和抗体和总抗体的快速上升。其他参与者有限的早期时间点没有评估补体激活。在AAV暴露后的早期时间点进行适当的监测,可以成功地控制TMA。然而,当使用基于raav的基因疗法治疗DMD时,这些早期事件应被认为与获益-风险状况有关。ClinicalTrials.gov识别码:NCT03362502。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
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.
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