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.

Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

“…This finding was in agreement with background levels of Hex in PBMCs after AAV therapy, 1.69% of normal (n=3), which is comparable to untreated controls (1.84% of normal, n=5). In contrast, substrate reduction therapy with miglustat substantially reduced LysoTracker levels in NPC [23], which may not be surprising since miglustat was administered systemically and gene therapy in the current study was administered intracranially.…”

“…te Vruchte et al demonstrated elevation of the acidic compartment of circulating CD19+ B cells, which correlated with age and disease progression [23]. Marked expansion of LysoTracker positive cells to nearly fivefold normal was demonstrated in PBMCs of SD cats as well.…”

“…Elevations of aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) have been noted in serum and CSF of patients with Tay-Sachs disease [18-20] and canine GM1 gangliosidosis [21]. After development in a mouse model of Niemann-Pick C (NPC) disease [22], a fluorescent, acidotropic probe (LysoTracker) has recently been validated as a biomarker in more than 100 NPC patients [23]. LysoTracker fluorescence increased with expansion of acidic compartments such as lysosomes, correlated with age and disease progression in untreated patients, and decreased in response to substrate reduction therapy.…”

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

“…5). The oxysterol concentrations in these samples had been measured by HPLC‐MS/MS 10 in a previous study 32. The magnitude of the correlation coefficients were 0.608 and 0.585, respectively, indicating that the bile acids and oxysterols are moderately correlated.…”

Secretory sphingomyelinase in health and disease

“…A SM-degrading enzyme with a slightly acidic pH optimum and a distinct pattern of activation by Co 2+ and Mn 2+ has been purified from bovine seminal plasma but is assumed to differ from S-ASM (Vanha-Perttula, 1988;Vanha-Perttula et al, 1990). In a mouse model of NPD type C, lysosomal enlargement in the brain -a feature of these lysosomal storage disorders -correlated with that in circulating B cells (te Vruchte et al, 2014). Thus, measuring the relative acidic compartment volume of these peripheral cells using a fluorescent probe may represent a surrogate marker for the progression of lipid storage in the brain.…”