ArticleJCI insight2019
Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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The trial behind it
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Who cites it
36 citing papers in PubMed, 44 citations in OpenAlex.
- Safety, efficacy, and patient-reported outcomes 6 years after fidanacogene elaparvovec in adults with hemophilia B.Blood advances · 2026Trial
- Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec.Thrombosis and haemostasis · 2024Trial
- Article
- A precision gene-engineered B cell medicine producing sustained levels of active factor IX for hemophilia B therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Chinese guidance for the clinical application of adeno-associated virus vector-based gene therapy for hemophilia B (2025).Blood science (Baltimore, Md.) · 2025Article
- Protease domain exosites regulate extravascular binding of factor IX(a).Journal of thrombosis and haemostasis : JTH · 2025Article
- Gene therapy as an innovative approach to the treatment of hemophilia B-a review.Journal of applied genetics · 2025Review
- Evaluation of One-Stage Assays for the Monitoring of Recombinant Human Factor IX Padua Activity After Etranacogene Dezaparvovec Gene Therapy.Haemophilia : the official journal of the World Federation of Hemophilia · 2025Article
- Current clinical applications of AAV-mediated gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- [Chinese guidance for the clinical application of Adeno-associated virus vector-based gene therapy for hemophilia B (2025)].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2025Article
- Blood Coagulation Factor IX: Structure, Function, and Regulation.IUBMB life · 2025Review
- Review
- Enhanced procoagulant activity of select hemophilia B causing factor IX variants with emicizumab.Blood · 2024Article
- Activated protein C resistance in the copresence of emicizumab and activated prothrombin complex concentrates.Research and practice in thrombosis and haemostasis · 2024Article
- Humanization and functional characterization of enhanced coagulation factor IX variants identified through ancestral sequence reconstruction.Journal of thrombosis and haemostasis : JTH · 2024Article
- Review
- Modulation of Extravascular Binding of Recombinant Factor IX Impacts the Duration of Efficacy in Mouse Models.Thrombosis and haemostasis · 2023Article
- CRISPR-Mediated In Situ Introduction or Integration ofInternational journal of molecular sciences · 2023Article
- Article
- Differences in wild-type- and R338L-tenase complex formation are at the root of R338L-factor IX assay discrepancies.Blood advances · 2023Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Adeno-associated-viral (AAV) vector liver-directed gene therapy (GT) for hemophilia B (HB) is limited by a vector-dose-dependent hepatotoxicity. Recently, this obstacle has been partially circumvented by the use of a hyperactive factor IX (FIX) variant, R338L (Padua), which has an eightfold increased specific activity compared to FIX-WT. FIX-R338L has emerged as the standard for HB GT. However, the underlying mechanism of its hyperactivity is undefined; as such, safety concerns of unregulated coagulation and the potential for thrombotic complications have not been fully addressed. To this end, we evaluated the enzymatic and clotting activity as well as the activation, inactivation, and cofactor-dependence of FIX-R338L relative to FIX-WT. We observed that the high-specific-activity of FIX-R338L requires factor VIIIa (FVIIIa) cofactor. In a novel system utilizing emicizumab, a FVIII-mimicking bispecific antibody, the hyperactivity of both recombinant FIX-R338L and AAV-mediated-transgene-expressed FIX-R338L from HB GT subjects is ablated without FVIIIa activity. We conclude that the molecular regulation of activation, inactivation, and cofactor-dependence of FIX-R338L is similar to FIX-WT, but that the FVIIIa-dependent hyperactivity of FIX-R338L is the result of a faster rate of factor X activation. This mechanism helps mitigate safety concerns of unregulated coagulation and supports the expanded use of FIX-R338L in HB therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.