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  1. Relative Acidic Compartment Volume as a Biomarker

Relative Acidic Compartment Volume as a Biomarker

Danielle Te Vruchte Anneliese O. Speak, PhD Kerri L. Wallom, PhD Nada Al Eisa, PhD David A. Smith Christian J. Hendriksz, MD Louise Simmons Robin H. Lachmann, PhD Alison Cousins Ralf Hartung Eugen Mengel, MD Heiko Runz, MD Prof. Michael Beck, MD Yasmina Amraoui, MD Jackie Imrie Elizabeth Jacklin Kate Riddick Nicole M. Yanjanin Christopher A. Wassif, PhD Prof. Arndt Rolfs, MD Florian Rimmele, MD Naomi Wright Prof. Clare Taylor, MD Uma Ramaswami, MD Timothy M. Cox, MD Caroline Hastings, MD Xuntian Jiang, PhD Rohini Sidhu Daniel S. Ory, MD Begoña Arias Novas Mylvaganam Jeyakumar, PhD Daniel J. Sillence, PhD James E. Wraith Forbes D. Porter, PhD Mario Cortina-Borja, PhD Frances M. Platt, PhD
March 01, 2014

Relative Acidic Compartment Volume as a Lysosomal Storage Disorder–Associated Biomarker

J Clin Invest. 2014;124(3):1320–1328. 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.