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高剂量全身 AAV 治疗中的致命免疫毒性。

Lethal immunotoxicity in high-dose systemic AAV therapy.

机构信息

Department of Molecular Microbiology and Immunology and Department of Neurology, School of Medicine, Department of Biomedical Sciences, College of Veterinary Medicine, Department of Chemical and Biomedical Engineering, College of Engineering, University of Missouri, Columbia, MO 65212, USA.

出版信息

Mol Ther. 2023 Nov 1;31(11):3123-3126. doi: 10.1016/j.ymthe.2023.10.015. Epub 2023 Oct 10.

DOI:10.1016/j.ymthe.2023.10.015
PMID:37822079
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10638066/
Abstract

High-dose systemic gene therapy with adeno-associated virus (AAV) is in clinical trials to treat various inherited diseases. Despite remarkable success in spinal muscular atrophy and promising results in other diseases, fatality has been observed due to liver, kidney, heart, or lung failure. Innate and adaptive immune responses to the vector play a critical role in the toxicity. Host factors also contribute to patient death. This mini-review summarizes clinical findings and calls for concerted efforts from all stakeholders to better understand the mechanisms underlying lethality in AAV gene therapy and to develop effective strategies to prevent/treat high-dose systemic AAV-gene-therapy-induced immunotoxicity.

摘要

高剂量系统性腺相关病毒（AAV）基因治疗正在临床试验中用于治疗各种遗传性疾病。尽管在脊髓性肌萎缩症方面取得了显著成功，并且在其他疾病方面也取得了有希望的结果，但由于肝脏、肾脏、心脏或肺部衰竭，仍观察到了死亡率。载体的固有和适应性免疫反应在毒性中起着关键作用。宿主因素也导致患者死亡。本综述总结了临床发现，并呼吁所有利益相关者共同努力，以更好地了解 AAV 基因治疗致死性的潜在机制，并制定有效的策略来预防/治疗高剂量系统性 AAV 基因治疗引起的免疫毒性。

相似文献

[1]
Lethal immunotoxicity in high-dose systemic AAV therapy.

Mol Ther. 2023-11-1

[2]
[How safe is gene therapy? : Second death after Duchenne therapy].

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[3]
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[4]
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[5]
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Mol Ther. 2021-11-3

[6]
Assessment of the Gene Therapy Immune Response in the Canine Muscular Dystrophy Model.

Methods Mol Biol. 2023

[7]
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[8]
Micro-Dystrophin Gene Therapy Goes Systemic in Duchenne Muscular Dystrophy Patients.

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[9]
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Nat Med. 2019-2-18

[10]
Enhanced CRISPR-Cas9 correction of Duchenne muscular dystrophy in mice by a self-complementary AAV delivery system.

Sci Adv. 2020-2-19

引用本文的文献

[1]
Fighting for every beat: cardiac therapies in Duchenne muscular dystrophy.

Skelet Muscle. 2025-9-9

[2]
Intravenous AAV9- plus subcutaneous copper histidinate optimizes outcomes in a lethal Menkes disease mouse model.

Sci Adv. 2025-8-29

[3]
Engineering Targeted Gene Delivery Systems for Primary Hereditary Skeletal Myopathies: Current Strategies and Future Perspectives.

Biomedicines. 2025-8-16

[4]
AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects.

Gene Ther. 2025-8-15

[5]
Trends and challenges of AAV-delivered gene editing therapeutics for CNS disorders: Implications for neurodegenerative disease.

Mol Ther Nucleic Acids. 2025-7-17

[6]
Novel Human Heart-Derived Natural Adeno-Associated Virus Capsid Combines Cardiospecificity With Cardiotropism In Vivo.

Circulation. 2025-8-12

[7]
Pharmacovigilance in Cell and Gene Therapy: Evolving Challenges in Risk Management and Long-Term Follow-Up.

Drug Saf. 2025-8-9

[8]
Advances and Challenges in Adeno-Associated Virus Gene Therapy Applications of Localized Delivery Strategies.

Curr Med Sci. 2025-7-15

[9]
A Compact Base Editor Rescues AATD-associated Liver and Lung Disease in Mouse Models.

bioRxiv. 2025-5-9

[10]
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本文引用的文献

[1]
Patient and Caregiver Outcomes After Onasemnogene Abeparvovec Treatment: Findings from the Cure SMA 2021 Membership Survey.

Adv Ther. 2023-12

[2]
An Overview of Nonclinical and Clinical Liver Toxicity Associated With AAV Gene Therapy.

Toxicol Pathol. 2023-10

[3]
Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy.

N Engl J Med. 2023-9-28

[4]
FDA approves first gene therapy for Duchenne muscular dystrophy, despite internal objections.

Nat Rev Drug Discov. 2023-8

[5]
Dystrophin Immunity after Gene Therapy for Duchenne's Muscular Dystrophy.

N Engl J Med. 2023-6-15

[6]
Duchenne Muscular Dystrophy Gene Therapy in 2023: Status, Perspective, and Beyond.

Hum Gene Ther. 2023-5

[7]
Immune Responses to Muscle-Directed Adeno-Associated Viral Gene Transfer in Clinical Studies.

Hum Gene Ther. 2023-5

[8]
Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings.

Gene Ther. 2023-9

[9]
Progress in Bioengineering of Myotropic Adeno-Associated Viral Gene Therapy Vectors.

Hum Gene Ther. 2023-5

[10]
Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'.

J Neuromuscul Dis. 2023

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