Correcting dominant‐negative von Willebrand disease

In this issue of the Journal Thrombosis and Haemostasis, Campioni et al report correction dominant‐negative von Willebrand disease (VWD) in vivo for first time. particular, they demonstrate that targeted inhibition a mutant VWF allele can significantly improve bleeding phenotype Type 2A VWD murine model. Collectively, these data move us another step closer to developing personalized approaches treatment patients extend beyond traditional factor (VWF) infusion therapy. Under normal conditions, majority plasma is derived from endothelial cell (EC) secretion.1.Lenting P.J. Christophe O.D. Denis C.V. biosynthesis, secretion, clearance: connecting far ends.Blood. 2015; 125: 2019-2028Crossref PubMed Scopus (234) Google Scholar Prior undergoes complex post‐translational modification within EC. endoplasmic reticulum (ER), monomers are assembled into dimers through formation C‐terminal disulphide bonds. Subsequently, form high molecular weight multimers (HMWM) Golgi after round N‐terminal bond formation.1.Lenting As result, circulates as series heterogeneous oligomers play key roles maintaining hemostasis (Figure 1A).2.Leebeek F.W. Eikenboom J.C. Von Willebrand's Disease.N Engl J Med. 2016; 375: 2067-2080Crossref (281) Scholar, 3.Laffan M.A. Lester W. O'Donnell J.S. al.The diagnosis management disease: United Kingdom Haemophilia Centre Doctors Organization guideline approved by British Committee Standards Haematology.Br Haematol. 2014; 167: 453-465Crossref (245) constitutes most common inherited disorder affects up 1 1000 individuals.2.Leebeek 4.Fogarty H. Doherty D. New developments disease.Br 2020; Crossref (16) The caused mutations at gene locus on chromosome 12.5.Goodeve A.C. genetic basis disease.Blood Rev. 2010; 24: 123-134Crossref (120) These affect biosynthesis EC variety different ways, ultimately leading either quantitative (Type VWD) or qualitative (Types 2A, 2B, 2M, 2N deficiencies consequent phenotype.6.de Jong A. J. mutation spectrum associated mechanisms.Thromb Res. 2017; 159: 65-75Abstract Full Text PDF (41) more than 90% cases, heterozygous nature.5.Goodeve Consequently, combination wild‐type synthesized together then linked hetero‐multimers 1B). This processing has important implications with respect understanding pathobiological mechanisms which exert their effects. For example, some cases VWD, incorporation growing polymer chain effectively prevents further multimerization, thereby loss 1B).7.Casari C. Pinotti M. Lancellotti S. deletion p. P1127_C1948delinsR: mechanism modulation.Blood. 116: 5371-5376Crossref (20) Recent vitro studies have investigated whether be used strategy correct VWD. Casari initially studied p.P1127_C1948delinsR COS‐1 cells.7.Casari When co‐expressed wild type (WT‐) VWF, variant (DEL‐VWF) exhibited effect, significant reductions antigen activity levels, well marked reduction HMWM. authors demonstrated small interfering RNAs (siRNAs) targeting novel breakpoint DEL‐VWF mRNA could restore attenuate effects 1C).7.Casari de also an siRNA approach dominant negative (p.Cys2773Ser) expressed HEK293 cells.8.de Dirven R.J. Oud J.A. Tio van Vlijmen B.J.M. Correction multimerization defect RNA‐mediated allele‐specific factor.J Thromb Haemost. 2018; 16: 1357-1368Crossref (13) study, were selected target single‐nucleotide polymorphisms (SNPs) present but absent allele.8.de SNP been primary colony‐forming cells (ECFCs) patient p.Cys1190Tyr (c.3569 G > A) mutation.9.de Boender al.Ex Improvement Disease Phenotype Using Allele‐Specific Small‐Interfering RNA.Thromb build upon previous findings. They generated model co‐expressing WT‐VWF (p.P1127_C1948delinsR) alleles VWF‐deficient mice using hydrodynamic transfer (HGT). resultant recapitulated abnormal multimer pattern, HMWM phenotype. two effort observed mouse First, treated siRNAs selectively (siDEL‐VWF). Administration siDEL‐VWF resulted partial phenotype, increase 25% VWF:Ag levels 1C). second approach, editing may role correcting To address hypothesis, introducing (p.C2773R) DEL was explored. missense impairs dimerization so retained ER 1D).10.Tjernberg P. Vos H.L. Spaargaren‐van Riel C.C. al.Differential intrachain‐ versus interchain‐disulfide bonds cystine‐knot domain clinical disease.Thromb 2006; 96: 717-724Crossref (21) contrast modest improvements following siDEL‐VWF, complete correction, such indistinguishable those seen WT controls. Furthermore, introduction normalization tail clip‐bleeding assay. Collectively findings suggest reduce production offer exciting treatment. A number aspects current study consider. HGT. expression hepatocytes had internalized plasmids, opposed secretion. efficacy therefore reflects RNA silencing rather develop further, methods enable will clearly required. Given heterogeneity exists between tissues, likely challenges.11.Kowalski P.S. Leus N.G. Scherphof G.L. Ruiters M.H. Kamps Molema G. Targeted delivery diseased microvascular cells: cellular concepts.IUBMB Life. 2011; 63: 648-658Crossref (32) 12.Nabzdyk C.S. Pradhan‐Nabzdyk L. LoGerfo RNAi therapy wall arteries veins: anatomical, physiologic, pharmacological considerations.J Transl 15: 164Crossref (11) Target choice, potential off‐target effects, cell/tissue specific remain major obstacles optimization methodology its ultimate use setting. addition, performed ex vivo. Once again, technical challenges need overcome order Nonetheless, presented undoubtedly provide biological proof concept VWD5.Goodeve 6.de low VWF13.Aguila Lavin Dalton N. al.Increased galactose enhanced clearance factor.Blood. 2019; 133: 1585-1596Crossref (25) 14.Flood V.H. Christopherson P.A. Gill al.Clinical laboratory variability cohort diagnosed States.Blood. 127: 2481-2488Crossref (79) corrected siRNA‐ DNA‐based approaches. direct relevance, particularly there relatively limited progress options over recent decades.3.Laffan 15.Lavin disease.Hematology Am Soc Hematol Educ Program. 2016: 683-689Crossref (19) 16.Lavin How I treat levels.Blood. 795-804Crossref (29) extending field range other disorders. declare no conflicts interest. EK JOD drafted version manuscript critically reviewed final manuscript. supported funds NIH Zimmerman Program (HL081588), Science Foundation Ireland Principal Investigator Award (11/PI/1066), Health Research Board Lead Project (ILP‐POR‐2017‐008), National Children's (C/18/1).National Institutes HealthHL081588Health BoardILP‐POR‐2017‐008Science Ireland11/PI/1066National Children’s CentreC/18/1