ArticleEMBO molecular medicine2020
Single-domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors.
Article in EMBO molecular medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- The Mirage of Factor Equivalence: Examining the Complexities of Non-Factor Therapies in Haemophilia.Haemophilia : the official journal of the World Federation of Hemophilia · 2025Review
- A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options.Haematologica · 2025Article
- Nanobodies: Robust miniprotein binders in biomedicine.Advanced drug delivery reviews · 2023Review
- RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection.Journal of blood medicine · 2023Review
- The Implication of New Developments in Hemophilia Treatment on Its Laboratory Evaluation.Cureus · 2022Review
- Review
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates.Nature communications · 2021Article
- A Small Virus to Deliver Small Antibodies: New Targeted Therapies Based on AAV Delivery of Nanobodies.Microorganisms · 2021Review
- Novel treatments for hemophilia through rebalancing of the coagulation cascade.Pediatric blood & cancer · 2021Review
- Skeletal muscle myosin and cardiac myosin attenuate heparin's antithrombin-dependent anticoagulant activity.Journal of thrombosis and haemostasis : JTH · 2021Article
- Camelid-derived single-chain antibodies in hemostasis: Mechanistic, diagnostic, and therapeutic applications.Research and practice in thrombosis and haemostasis · 2020Review
- Laboratory monitoring of hemophilia A treatments: new challenges.Blood advances · 2020Review
- Antithrombin inhibition using nanobodies to correct bleeding in hemophilia.EMBO molecular medicine · 2020Article
- Single-domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors.EMBO molecular medicine · 2020Article
- Serpins in Hemostasis as Therapeutic Targets for Bleeding or Thrombotic Disorders.Frontiers in cardiovascular medicine · 2020Review
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
Novel therapies for hemophilia, including non-factor replacement and in vivo gene therapy, are showing promising results in the clinic, including for patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama-derived single-domain antibody fragments (sdAbs) able to restore hemostasis by inhibiting the antithrombin (AT) anticoagulant pathway. We demonstrated that sdAbs engineered in multivalent conformations were able to block efficiently AT activity in vitro, restoring the thrombin generation potential in FVIII-deficient plasma. When delivered as a protein to hemophilia A mice, a selected bi-paratopic sdAb significantly reduced the blood loss in a model of acute bleeding injury. We then packaged this sdAb in a hepatotropic AAV8 vector and tested its safety and efficacy profile in hemophilic mouse models. We show that the long-term expression of the bi-paratopic sdAb in the liver is safe and poorly immunogenic, and results in sustained correction of the bleeding phenotype in hemophilia A and B mice, even in the presence of inhibitory antibodies to the therapeutic clotting factor.
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