Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker

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dc.contributor.authorte Vruchte, Danielleen
dc.contributor.authorSpeak, Anneliese O.en
dc.contributor.authorWallom, Kerri L.en
dc.contributor.authorAl Eisa, Nadaen
dc.contributor.authorSmith, David A.en
dc.contributor.authorHendriksz, Christian J.en
dc.contributor.authorSimmons, Louiseen
dc.contributor.authorLachmann, R. H.en
dc.contributor.authorCousins, Alisonen
dc.contributor.authorHartang, Ralfen
dc.contributor.authorMengel, Eugenen
dc.contributor.authorRunz, Heikoen
dc.contributor.authorBeck, Michealen
dc.contributor.authorAmraoui, Yasminaen
dc.contributor.authorImrie, Jackieen
dc.contributor.authorJacklin, Elizabethen
dc.contributor.authorRiddick, Kateen
dc.contributor.authorYanjanin, Nicole M.en
dc.contributor.authorWassif, Christopher A.en
dc.contributor.authorRolfs, Arndten
dc.contributor.authorRimmele, Florianen
dc.contributor.authorWright, Naomien
dc.contributor.authorTaylor, Clareen
dc.contributor.authorRamaswami, Umaen
dc.contributor.authorCox, Timothy M.en
dc.contributor.authorHastings, Carolineen
dc.contributor.authorJiang, Xuntianen
dc.contributor.authorSidhu, Rohinien
dc.contributor.authorOry, Daniel S.en
dc.contributor.authorArias, Begonaen
dc.contributor.authorJeyakumar, Mylvaganamen
dc.contributor.authorSillence, Daniel J.en
dc.contributor.authorWraith, James E.en
dc.contributor.authorPorter, Forbes D.en
dc.contributor.authorCortina-Borja, Marioen
dc.contributor.authorPlatt, Frances M.en
dc.date.accessioned2014-03-28T11:37:50Z
dc.date.available2014-03-28T11:37:50Z
dc.date.issued2014-03-03
dc.description.abstractLysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.en
dc.funderAction Medical Researchen
dc.identifier.citationte Vruchte, D. et al. (2014) Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker. Journal of Clinical Investigation, 124 (3), pp. 1320–1328en
dc.identifier.doihttps://doi.org/10.1172/JCI72835
dc.identifier.urihttp://hdl.handle.net/2086/9855
dc.language.isoenen
dc.peerreviewedYesen
dc.projectidSP4203 and SP3775en
dc.researchgroupPharmacologyen
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.subjectNiemann-Pick Cen
dc.subjectLysosomeen
dc.subjectLysotrackeren
dc.subjectLysosomal storage diseaseen
dc.subjectGlycolipiden
dc.titleRelative acidic compartment volume as a lysosomal storage disorder–associated biomarkeren
dc.typeArticleen

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