Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker.
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
D
te Vruchte
Anneliese O
AO
Speak
Kerri L
KL
Wallom
Nada
N
Al Eisa
David A
DA
Smith
Christian J
CJ
Hendriksz
Louise
L
Simmons
Robin H
RH
Lachmann
Alison
A
Cousins
Ralf
R
Hartung
Eugen
E
Mengel
Heiko
H
Runz
Michael
M
Beck
Yasmina
Y
Amraoui
Jackie
J
Imrie
Elizabeth
E
Jacklin
Kate
K
Riddick
Nicole M
NM
Yanjanin
Christopher A
CA
Wassif
Arndt
A
Rolfs
Florian
F
Rimmele
Naomi
N
Wright
Clare
C
Taylor
Uma
U
Ramaswami
Timothy M
TM
Cox
Caroline
C
Hastings
Xuntian
X
Jiang
Rohini
R
Sidhu
Daniel S
DS
Ory
Begona
B
Arias
Mylvaganam
M
Jeyakumar
Daniel J
DJ
Sillence
James E
JE
Wraith
Forbes D
FD
Porter
Mario
M
Cortina-Borja
Frances M
FM
Platt
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000473:pathology* / Q000628:therapy; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D012720:Severity of Illness Index; D016896:Treatment Outcome; D047392:beta-Cyclodextrins / Q000627:therapeutic use
D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D017485:1-Deoxynojirimycin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C059896:miglustat