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

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

Abstract

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.

Authors

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

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Figure 4

Relative LE/Lys volume is a sensitive measure of response and potentially adverse response to NPC disease therapeutics.

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Relative LE/Lys volume is a sensitive measure of response and potentiall...
(A) Pre-post analysis of an NPC2 patient with BMT, using Lysotracker analysis of circulating B cells. MEFL was reduced 1 month after BMT, and by 3 months was within the pediatric control range. At 3 months after BMT, donor chimerism developed and was detected by the presence of 2 B cell populations (inset; gated on mononuclear cells). The populations had high or low Lysotracker fluorescence, with a 50:50 distribution of B cells between the 2 populations. HLA typing confirmed the development of 50% donor chimerism (not shown). (B) 7 patients on HPβCD therapy (individual use INDs) were analyzed. Patients 1–4 were analyzed pre-post i.v. HPβCD (arrows denote therapy initiation points), patients 5 and 6 were analyzed after HPβCD only, and patient 7 was analyzed pre-post intrathecal HPβCD delivery (no i.v. administration throughout the treatment period). (C) B cells isolated from the blood of patients 1–4 were analyzed to determine their levels of GSL storage. Total GSL levels were compared before and after HPβCD delivery for each patient and plotted individually (blue; error bars derived from 3 independent HPLC analytical runs of the same samples). An average of the 4 patients was also plotted (green; error bars derived from the mean values for each patient). *P < 0.05; ***P < 0.001.