RNA-targeted therapy for von Willebrand Disease
Von Willebrand disease (VWD) is the most common inherited bleeding disorder caused by qualitative or quantitative defects of von Willebrand factor (VWF). VWD has a prevalence of about 1 in 10,000 for patients with clinically relevant bleeding. Patients mainly suffer from mucocutaneous, post-traumatic or surgical bleeding, the more severe forms are associated with joint bleeds, thrombocytopenia or vascular malformations like gastrointestinal angiodysplasia.
Current treatment of VWD is focussed on increasing VWF plasma levels through administration of desmopressin or VWF-containing concentrates. However, in multiple situations these treatment strategies lack efficiency, since the production of mutant VWF is not dealt with. For example, the unhindered presence of mutant VWF may have negative effects like thrombocytopenia or the development of intestinal angiodysplasia. As most VWD (more than 90 per cent) is caused by dominant-negative missense mutations in VWF, a LUMC researcher hypothesized that the clinical phenotype may be ameliorated by diminishing expression of the mutant VWF allele.
The researcher has developed an approach and proved the principle of allele-specific inhibition of the mutant VWF allele by applying small interfering RNAs (siRNAs) targeting common single nucleotide polymorphisms (SNPs) in VWF. With a small set of SNPs, they are able to target a high percentage of patients, which would not be possible if each of the many identified VWD-related mutations is targeted.
- Efficient and allele-specific siRNAs against common SNPs in VWF have been selected
- Proof-of-principle for in vitro correction of a severe phenotypic (multimerization) defect has been shown
- Based on the frequency of the SNPs in the Caucasian population this siRNA approach may be applicable in over 75% of the VWD population
To be published very soon in peer-reviewed journal.
The researcher is seeking industry partners interested in developing this technology further, with the ultimate goal of treating the patients with the disease.
Luris reference numberINV-0072.0623
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