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.
Danielle te Vruchte, Anneliese O. Speak, Kerri L. Wallom, Nada Al Eisa, David A. Smith, Christian J. Hendriksz, Louise Simmons, Robin H. Lachmann, Alison Cousins, Ralf Hartung, Eugen Mengel, Heiko Runz, Michael Beck, Yasmina Amraoui, Jackie Imrie, Elizabeth Jacklin, Kate Riddick, Nicole M. Yanjanin, Christopher A. Wassif, Arndt Rolfs, Florian Rimmele, Naomi Wright, Clare Taylor, Uma Ramaswami, Timothy M. Cox, Caroline Hastings, Xuntian Jiang, Rohini Sidhu, Daniel S. Ory, Begona Arias, Mylvaganam Jeyakumar, Daniel J. Sillence, James E. Wraith, Forbes D. Porter, Mario Cortina-Borja, Frances M. Platt
Relative LE/Lys volume increases progressively in B cells in a mouse model of NPC1 disease and parallels the rate of GSL storage in the brain.