A pilot study to explore plasma abnormalities as possible biomarkers in patients with acid sphingomyelinase deficiency (ASMD)

Acid sphingomyelinase deficiency (ASMD), also known as Niemann Pick disease
type A and B, is a rare lysosomal storage disease characterized by an
autosomal recessive inherited deficiency of acid sphingomyelinase (ASMase).
This results in lysosomal accumulation of sphingomyelin (SM) primarily in
macrophages. In addition, recent research indicates that this defect influences
the proper function of the endosome-lysosome system. Key feature is the
accumulation of sphingolipids, predominantly SM as well as cholesterol in
spleen, liver, lungs and other organs .
The pathophysiology of ASMD is only partially understood. Key feature is the
formation of pathological lipid-laden macrophages in spleen, liver and lungs
and other organs which likely leads to a chronic low-grade inflammatory state
as demonstrated by slightly elevated ceramide levels in these patients. The
close connection between levels of SM, ceramide and endosomal/lysosomal
cholesterol transport suggests that altered cholesterol transport also
impacts lysosomal storage of SM and related sphingolipids.
Treatment consists of supportive care. However, enzyme replacement therapy with
recombinant human acid sphingomyelinase is currently under clinical evaluation
in the ASCEND trial, an international phase II/III randomized controlled trial
in which the AMC is a participating center.This potential new treatment option
is an excellent opportunity to explore the presence of plasma abnormalities
which may prove to be of value in the identification of potential biomarkers.

Primary objective
To investigate the presence of plasma abnormalities in treated and untreated
patients with ASMD to determine whether they can potentially serve as useful
biomarker . Therefore we will determine
- sphingolipids and *metabolites
- macrophage markers chitotriosidase and CCL-18
- pro- and anti-inflammatory cytokines
- surfactant protein A and D, KL-6, YKL-40 , CC16 and cCK18 as markers of
pulmonary involvement
- lipid profiles including cholesterol, HDL, LDL and apolipoproteins as well as
the oxysterols 7-KC and C-triol

This pilot-study is a prospective observational study of a cohort of ASMD
patients , both untreated patients and patients receiving enzyme replacement
therapy as part of the ASCEND trial. All ASMD patients known in the Academic
Medical Center (AMC) will be contacted to participate in this study. In this
study plasma abnormalities will be studied in ASMD patients over a period of 24
months. The amount of frequency of additional plasma samples is dependent on
when a patient is also participating in the ASCEND trial.

In untreated patients plasma samples will be obtained every 6 months during a
period of 24 months. This will be scheduled on the same day as their routine
appointments, which often already includes a blood collection through
venipuncture.
In treated patients, who  will be receiving infusions every other  week as part
of the ASCEND trial,  additional plasma samples will be drawn.
For analysis of sphingolipids and *metabolites , macrophage markers, cytokines
and oxysterols 2 ml of extra blood will be drawn at week 0,10,14,26 and 52
right before during and directly after infusion as well as 1 hour, 4 hours, 8
hours and 24 hours after infusion.
To determine markers of lung involvement 14ml of blood will be drawn right
before infusion at week 0 , 52, 80 and 104. Finally 4,5 ml of extra blood for
lipid profiles will be obtained right before and 24 hours after infusion at
week 0, 26, 52, 80 and 104.





 

Patients participating in this study will all be diagnosed with ASMD and
therefore will visit our hospital regularly for routine check-ups. When
patients are also participating in the ASCEND enzyme replacement trial they
will visit our hospital regularly since they will be receiving infusions every
two weeks For this pilot study we require additional blood samples to be
collected during routine check-up visits or study visits. Therefore no extra
site visits for this study are necessary and when possible blood collections
through venipuncture will be combined with those as part of a routine (study)
visit.
The risk of blood collection through venipuncture is considered minimal but may
include soreness, bleeding or infection .