von Willebrand disease: what does the future hold?

Abstract

Von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal to reach superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches such as gene therapy using dual-vector adeno-associated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase FVIII levels in VWD-type 3 or 2N patients will be discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired Von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) will be presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.

Structural basis of von Willebrand factor multimerization and tubular storage

“…Careful review of literature revealed a delicate study on the type 2A VWD associated VWF-437-442 mutant 43 . This mutant has lost the ability to form multimers and has defects in regulated storage, but co-expressed normal D1D2 completely restored multimerization of the mutant 43 Despite current clinical management of VWD being considered effective with limited innovation in terms of treatment over last 30 years, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women 5 . As the VWD is an ideal target for gene therapy where a single treatment could potentially result in long term correction of the disease and even partial correction could have benefits in lowering the bleeding risks, like in the case of hemophilia 44 .…”

“…Its normal function requires the assembly of VWF into large disulfide-linked multimers [1][2][3] . Defects in VWF multimerization cause several forms of von Willebrand disease (VWD), the most common inherited bleeding disorder worldwide [4][5][6][7] .…”

Towards novel treatment options in von Willebrand disease

“…In this review, we described two options, which at the relative short term could become available for these patients. A more extensive description of the different opportunities for innovation was published in 2021 10 . These innovative paths are not only limited to protein‐based strategies but also genetic approaches are in early stage preclinical development.…”

“…A more extensive description of the different opportunities for innovation was published in 2021. 10 These innovative paths are not only limited to protein-based strategies but also genetic approaches are in early stage preclinical development. With genetic approaches, one should think of siRNA-based techniques to silence mutant alleles or even gene therapy.…”

“…These studies consistently teach us that severe and moderate VWD patients have statistically significant reductions in nearly all health related quality-of-life domains, both physically and mentally (reviewed in Denis et al). 10 These results have not changed over the last 25 years. [11][12][13] In particular, women express considerable morbidity in emotion and pain.…”