In this video lecture, Dr. Peter Lenting discusses:
- Why innovation in von Willebrand disease therapeutics has lagged behind other bleeding disorders and why new treatment approaches remain needed.
- Emerging therapies that bypass factor VIII deficiency, increase endogenous von Willebrand factor levels, or target specific molecular mechanisms.
- Experimental gene therapy and gene-editing strategies that may enable personalized or potentially curative treatments for von Willebrand disease.
Dr. Peter J. Lenting obtained his PhD cum laude at the University of Amsterdam in 1996, while working at Sanquin Research. After holding positions as associate-professor of Hematology at the University Medical Center in Utrecht (2000-2007) and Director Protein/Antibody Discovery at Crucell Holland (2007-2009), Dr. Lenting works since 2009 as Director of Research at Inserm (DR-CE). His research focuses on fundamental and translational aspects of Hemophilia and von Willebrand disease. He has published >225 articles and is inventor on 16 patent applications.
He served as elected member at the council of the International Society of Thrombosis & Hemostasis (2012-2018) and the French Society of T & H (2017-2023), was chairman of the ISTH-WHO Standard Liaison group (2012-2018) and frequently participates in scientific advisory board meetings of pharmaceutical organizations. Dr. Lenting received the Prix Danièle Hermann (Institut de France) in 2009, the Arosenius Award (World Federation of Hemophilia) in 2022 and the van Creveld Medal (Dutch Society of T & H) in 2022 for his research activities.
(Video Lecture Summary)
Introduction
Dr. Peter Lenting explores the evolving landscape of novel therapies for von Willebrand disease (VWD). Although current treatments such as desmopressin and von Willebrand factor (VWF) concentrates have remained the standard of care for decades, he argues that they do not fully address the needs of many patients. Drawing on both clinical experience and emerging research, he reviews innovative therapeutic strategies designed to improve quality of life, expand treatment options, and ultimately move toward personalized and potentially curative therapies.
Why Innovation Is Needed
Dr. Lenting begins by asking why therapeutic innovation in VWD has progressed more slowly than in hemophilia. He suggests several contributing factors.
Many clinicians view existing therapies as generally effective, particularly in healthcare systems where concentrates and desmopressin are readily available. In addition, major bleeding episodes are often less frequent than in hemophilia, leading to the perception that fewer patients require long-term prophylaxis. He also notes broader challenges, including lower research funding for diseases that disproportionately affect women and the biological complexity of VWF itself, which makes therapeutic development more difficult than for smaller coagulation proteins such as factor VIII or factor IX.
From the patient’s perspective, however, important unmet needs remain. Frequent nosebleeds, bruising, heavy menstrual bleeding, and other recurrent bleeding symptoms can substantially affect quality of life despite not always being life-threatening. Dr. Lenting emphasizes that improvements in daily functioning and quality of life should be considered major therapeutic goals alongside prevention of severe bleeding.
Emerging Therapeutic Strategies
Dr. Lenting organizes novel therapies into three broad categories.
The first aims to compensate for the secondary factor VIII deficiency that accompanies many forms of VWD. The second seeks to increase endogenous VWF levels in patients with quantitative deficiencies, particularly type 1 disease. The third focuses on genetic approaches that could eventually provide personalized or potentially curative therapies.
Bypassing Factor VIII Deficiency
Because VWF stabilizes circulating factor VIII, VWF deficiency results in secondary factor VIII deficiency. Dr. Lenting discusses whether correcting factor VIII activity alone might improve hemostasis, even if the underlying VWF deficiency remains.
One approach involves efanesoctocog alfa, an engineered factor VIII molecule designed to circulate independently of VWF. Structural modifications allow the molecule to avoid rapid clearance while substantially prolonging its half-life. Early pharmacokinetic studies demonstrate preserved half-life even in patients with type 2N and type 3 VWD, where normal VWF-mediated stabilization is absent.
He also reviews experience with emicizumab, the bispecific antibody currently used in hemophilia A. Although used off-label, published case reports in patients with type 3 VWD describe marked reductions in spontaneous mucocutaneous and joint bleeding following treatment. Similar improvements have been observed in VWF-deficient mouse models.
A third strategy targets the natural anticoagulant protein S. Dr. Lenting discusses VGA039, a monoclonal antibody that promotes thrombin generation by reducing anticoagulant activity. Early clinical studies have demonstrated reductions in annual bleeding rates, suggesting another potential means of improving hemostasis without directly replacing VWF.
He emphasizes, however, that these approaches primarily correct factor VIII deficiency. Because they do not restore the diverse biologic functions of VWF itself, bleeding related specifically to VWF deficiency may still occur under certain clinical circumstances.
Increasing Endogenous VWF Levels
For patients with type 1 VWD, increasing endogenous VWF may offer a more physiologic treatment strategy.
Dr. Lenting describes a bispecific nanobody developed in his laboratory that simultaneously binds VWF and albumin. By linking endogenous VWF to albumin, the molecule exploits the neonatal Fc receptor (FcRn) recycling pathway, prolonging VWF survival in the circulation after a single subcutaneous injection.
In mouse models of type 1 VWD, this approach increased endogenous VWF and factor VIII levels for more than two weeks while preserving the normal multimer distribution. Importantly, the prolonged increase in VWF translated into correction of the bleeding phenotype in experimental models.
He also reviews another investigational monoclonal antibody directed against the VWF CK domain that similarly extends endogenous VWF survival. Early nonhuman primate studies demonstrated sustained increases in circulating VWF following a single subcutaneous dose, and phase 1 clinical trials are currently underway.
These FcRn-based approaches offer the possibility of infrequent subcutaneous administration while maintaining endogenous VWF function and multimer structure.
Genetic Approaches
The final portion of the lecture examines emerging genetic therapies for VWD.
Traditional adeno-associated virus (AAV) gene therapy has proven difficult because the VWF coding sequence exceeds the carrying capacity of standard AAV vectors. In addition, many patients harbor dominant-negative mutations that complicate simple gene replacement.
To address these limitations, investigators have developed several experimental strategies. One approach divides the VWF coding sequence between two AAV vectors that recombine after delivery into endothelial cells. Although this method successfully generated VWF expression in experimental models, expression levels remain too low for clinical application.
Another strategy focuses on replacing only specific functional portions of the VWF molecule. Dr. Lenting highlights studies in type 2A VWD demonstrating that expression of the normal VWF propeptide restores multimer formation and improves collagen and platelet binding.
Gene Editing and Allele-Specific Silencing
Dr. Lenting also reviews emerging precision genetic approaches designed to selectively eliminate disease-causing alleles.
Using CRISPR-Cas9 gene editing, investigators have successfully disrupted dominant-negative VWF mutations in endothelial colony-forming cells derived from patients with type 2A VWD. Gene editing restored normal Weibel-Palade body formation, suggesting correction of the underlying cellular defect.
A related strategy uses endothelial-targeted small interfering RNA (siRNA) to selectively silence mutant VWF transcripts while preserving expression from the normal allele. In mouse models of type 2B VWD, allele-specific silencing reduced incorporation of mutant VWF into multimers, restored high-molecular-weight multimers, and improved collagen binding.
Although these approaches remain in the preclinical stage, Dr. Lenting believes they illustrate the potential for subtype-specific and personalized treatment strategies that directly address the underlying molecular defect.
Conclusion
Dr. Lenting concludes that therapeutic innovation in VWD is entering a new phase. Emerging strategies seek not only to replace missing VWF but also to bypass secondary factor VIII deficiency, prolong endogenous VWF survival, and selectively correct disease-causing genetic variants. While many of these approaches remain experimental, they have the potential to improve quality of life, expand treatment options, and eventually provide personalized or curative therapies tailored to individual VWD subtypes.