ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
Engineered IgM and IgG cleaving enzymes for mitigating antibody neutralization and complement activation in AAV gene transfer.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- VTX-PID as a novel recombinant immunoglobulin G-degrading enzyme (IdeS) for efficient AAV-based gene therapy in participants with neutralizing antibodies: results of the phase I first-in-human NAVIgATE study.Frontiers in immunology · 2026Trial
- NF-κB-driven immune checkpoint knockdown and cytokine expression in cancer cells for tumor immunotherapy.iScience · 2026Article
- Targeted AAV gene therapy for neuroblastoma via direct capsid-antibody coupling.EMBO molecular medicine · 2026Article
- Cancer cell-selective ectopic expression of CD20 as an antigen enables rituximab repurposing for solid tumour immunotherapy.Clinical and translational medicine · 2026Article
- The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.The Biochemical journal · 2026Review
- Preclinical pharmacology and toxicology study of an AAV8-tATP7B vector for Wilson's disease.Clinical and molecular hepatology · 2026Article
- Delivery Systems for Therapeutic Genome Editing: Challenges, Innovations, and Future Perspectives.MedComm · 2026Review
- A novel immunoglobulin G- and immunoglobulin cleaving enzyme MG (IceMG), for antibody-mediated rejection.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2026Article
- Environmental and developmental factors shape anti-AAV immunity in pigs.Gene therapy · 2026Article
- Safety of Adeno-Associated Viral Vectors in Gene Therapy: Mechanisms of Toxicity, Clinical Risks, and Strategies for Their Minimization.International journal of molecular sciences · 2026Review
- Review
- Depletion and recovery of IgG following treatment with an anti-FcRn antibody and IdeS in pigtail macaques.Clinical and experimental immunology · 2026Article
- Current Status of Clinical Gene Therapy for Hemophilia and Globin Disorders.Journal of blood medicine · 2026Review
- Pre-Existing Anti-Adeno-Associated Virus Immunity in Gene Therapy: Mechanisms, Challenges, and Potential Solutions.Human gene therapy · 2025Review
- Emerging Technologies Tackling Adeno-Associated Viruses (AAV) Immunogenicity in Gene Therapy Applications.Pharmaceutics · 2025Review
- Depletion and recovery of IgG following treatment with Rozanoliximab and Imlifidase in pigtail macaques.bioRxiv : the preprint server for biology · 2025Article
- Circular RNA-based protein replacement therapy mitigates osteoarthritis in male mice.Nature communications · 2025Article
- Nonclinical strategies and considerations to enable the redosing of gene therapies.Molecular therapy. Methods & clinical development · 2025Review
- Use of CD19-targeted immune modulation to eradicate AAV-neutralizing antibodies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy.International journal of molecular sciences · 2025Review
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8 authors.
Funding
Abstract
Systemic dosing of adeno-associated viral (AAV) vectors poses potential risk of adverse side effects including complement activation triggered by anti-capsid immunity. Due to the multifactorial nature of toxicities observed in this setting, a wide spectrum of immune modulatory regimens are being investigated in the clinic. Here, we discover an IgM cleaving enzyme (IceM) that degrades human IgM, a key trigger in the anti-AAV immune cascade. We then engineer a fusion enzyme (IceMG) with dual proteolytic activity against human IgM and IgG. IceMG cleaves B cell surface antigen receptors and inactivates phospholipase gamma signaling in vitro. Importantly, IceMG is more effective at inhibiting complement activation compared with an IgG cleaving enzyme alone. Upon IV dosing, IceMG rapidly and reversibly clears circulating IgM and IgG in macaques. Antisera from these animals treated with IceMG shows decreased ability to neutralize AAV and activate complement. Consistently, pre-conditioning with IceMG restores AAV transduction in mice passively immunized with human antisera. Thus, IgM cleaving enzymes show promise in simultaneously addressing multiple aspects of anti-AAV immunity mediated by B cells, circulating antibodies and complement. These studies have implications for improving safety of AAV gene therapies and possibly broader applications including organ transplantation and autoimmune diseases.
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