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dc.contributor.authorVerhelle, Adriaan
dc.contributor.authorNair, Nisha
dc.contributor.authorEveraert, Inge
dc.contributor.authorVan Overbeke, Wouter
dc.contributor.authorSupply, Lynn
dc.contributor.authorZwaenepoel, Olivier
dc.contributor.authorPeleman, Cindy
dc.contributor.authorVan Dorpe, Jo
dc.contributor.authorLahoutte, Tony
dc.contributor.authorDevoogdt, Nick
dc.contributor.authorDerave, Wim
dc.contributor.authorChuah, Marinee K
dc.contributor.authorDriessche, Thierry Vanden
dc.contributor.authorGettemans, Jan
dc.date.accessioned2020-05-01T05:25:08Z
dc.date.available2020-05-01T05:25:08Z
dc.date.issued2017
dc.identifier.issn0964-6906
dc.identifier.doi10.1093/hmg/ddx056
dc.identifier.urihttp://hdl.handle.net/10072/393553
dc.description.abstractGelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+  binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at the surface. During secretion of mutant plasma gelsolin consecutive cleavage by furin and MT1-MMP results in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies that are able to (partly) inhibit furin or MT1-MMP proteolysis have previously been reported. In this study, the nanobodies have been combined into a single bispecific format able to simultaneously shield mutant plasma gelsolin from intracellular furin and extracellular MT1-MMP activity. We report the successful in vivo expression of this bispecific nanobody following adeno-associated virus serotype 9 gene therapy in gelsolin amyloidosis mice. Using SPECT/CT and immunohistochemistry, a reduction in gelsolin amyloid burden was detected which translated into improved muscle contractile properties. We conclude that a nanobody-based gene therapy using adeno-associated viruses shows great potential as a novel strategy in gelsolin amyloidosis and potentially other amyloid diseases.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherOXFORD UNIV PRESS
dc.relation.ispartofpagefrom1353
dc.relation.ispartofpageto1364
dc.relation.ispartofissue7
dc.relation.ispartofjournalHuman Molecular Genetics
dc.relation.ispartofvolume26
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiochemistry & Molecular Biology
dc.subject.keywordsGenetics & Heredity
dc.subject.keywordsADENOASSOCIATED VIRAL VECTORS
dc.titleAAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationVerhelle, A; Nair, N; Everaert, I; Van Overbeke, W; Supply, L; Zwaenepoel, O; Peleman, C; Van Dorpe, J; Lahoutte, T; Devoogdt, N; Derave, W; Chuah, MK; Driessche, TV; Gettemans, J, AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model, Human Molecular Genetics, 2017, 26 (7), pp. 1353-1364
dcterms.dateAccepted2017-02-07
dc.date.updated2020-05-01T05:13:47Z
gro.hasfulltextNo Full Text
gro.griffith.authorDerave, Wim


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