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

• Published in: The Journal of clinical investigation Vol. 124; no. 3; pp. 1320 - 1328
• Main Authors: te Vruchte, Danielle, Speak, Anneliese O., Wallom, Kerri L., Al Eisa, Nada, Smith, David A., Hendriksz, Christian J., Simmons, Louise, Lachmann, Robin H., Cousins, Alison, Hartung, Ralf, Mengel, Eugen, Runz, Heiko, Beck, Michael, Amraoui, Yasmina, Imrie, Jackie, Jacklin, Elizabeth, Riddick, Kate, Yanjanin, Nicole M., Wassif, Christopher A., Rolfs, Arndt, Rimmele, Florian, Wright, Naomi, Taylor, Clare, Ramaswami, Uma, Cox, Timothy M., Hastings, Caroline, Jiang, Xuntian, Sidhu, Rohini, Ory, Daniel S., Arias, Begona, Jeyakumar, Mylvaganam, Sillence, Daniel J., Wraith, James E., Porter, Forbes D., Cortina-Borja, Mario, Platt, Frances M.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2014
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - therapeutic use; 2-Hydroxypropyl-beta-cyclodextrin; Age; Animals; B-Lymphocytes - pathology; beta-Cyclodextrins - therapeutic use; Biological markers; Biomarkers; Biomedical research; Blood & organ donations; Bone Marrow Transplantation; Care and treatment; Case-Control Studies; Child; Child, Preschool; Diagnosis; Disease; Epidemiology; Humans; Identification and classification; Immune system; Infant; Intracellular Signaling Peptides and Proteins; Lysosomes - pathology; Medical case management; Medical research; Medicine, Experimental; Metabolism, Inborn errors of; Mice; Mice, Inbred BALB C; Mice, Knockout; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C - pathology; Niemann-Pick Disease, Type C - therapy; Pediatrics; Prospective Studies; Proteins - genetics; Severity of Illness Index; Studies; Technical Advance; Treatment Outcome; University colleges
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI72835

Lysosomal 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.