Systemic inflammation in ALSP patients and the effect of an allogenic hematopoietic stem cell transplantation on the inflammation

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
is a progressive neurodegenerative white matter disease (leukodystrophy), which
primarily affects adults between 30 and 50 years. The disease often starts with
neuropsychiatric features, followed by progressive motor and gait disturbances,
incontinence, speech and swallowing problems, epilepsy, and premature death
with a median survival of 6.8 years after onset of symptoms. The disease is
caused by dominant mutations in the gene CSF1R, encoding colony stimulating
factor-1 receptor (CSF-1R). CSF-1R acts as a receptor for cytokines, including
CSF-1 and IL-34. These cytokines regulate the production, differentiation and
function of various immune cells in the blood and brain, such as macrophages
and microglia. In addition, the microglia homeostasis is dependent on CSF-1R.
The disease is therefore characterized by microglia loss, resulting in
demyelination, axonal loss and inflammation in the central nervous system.

At present, ALSP patients are treated with an allogeneic hematopoietic stem
cell transplantation (HCT), if diagnosed rather early in the disease course.
The theory behind allogenic HCT is that hematopoietic stem cells from bone
marrow, peripheral blood or umbilical cord blood of a healthy donor are able to
cross the blood-brain barrier, and differentiate into healthy
macrophages/microglia to replace the (diseased) patient microglia. There is
increasing evidence that HCT may halt disease progression in ALSP patients, but
the long-term therapeutic effects are still unknown. The treatment has been
proven to be safe and halt disease progression if applied early in the disease
in several other leukodystrophies, including metachromatic leukodystrophy and
adrenoleukodystrophy, if stable engraftment following HCT has been
accomplished. In addition, there is growing recognition that a significant part
of the therapeutic effect of HCT in leukodystrophy patients comes from reducing
inflammation in the central nervous system, and that HCT also reduces systemic
inflammation in patients with a metabolic disorders with or without central
nervous system involvement. We expect that the anti-inflammatory effects of HCT
in ALSP patients might be even greater since the disease affects in particular
microglia, the immune cells of the central nervous system, and results in loss
of one of the most prevalent cytokine receptors present on immune cells in
blood of healthy humans. Nevertheless, scientific data on systemic inflammation
and in cytokine profiles in ALSP patients are currently lacking. Therefore, the
aims of this study are to examine the degree of systemic inflammation in ALSP
patients before and after HCT. The results could inform the pathophysiology and
treatment of ALSP, and might also be used for patient monitoring before and
after treatment, and to evaluate treatment effects. In addition, results of
this study could also inform the pathophysiology and treatment of other
metabolic neurodegenerative diseases, such as Krabbe disease and Gaucher
disease.

The aims of this study are to examine the degree of systemic inflammation in
ALSP patients, and whether there is a change in the degree of systemic
inflammation after treatment with an allogeneic HCT.

Primary research questions:
1. Are cytokine profiles in blood of ALSP patients before HCT different from
cytokine profiles in blood of healthy individuals?
2. How do cytokine profiles in blood of ALSP patients change over time after
treatment with HCT?

Secondary research questions:
1. Are changes in cytokine profiles in blood after treatment with HCT related
to clinical outcomes?

The study uses a longitudinal cohort study design. It is a multi-center study
that will be performed at the Department of Child Neurology in the Amsterdam
UMC, location VU medical center (VUmc) (primary site) and in the Emma
Children*s Hospital, Amsterdam UMC, location Amsterdam Medical Center (AMC),
Amsterdam, The Netherlands. Since most Dutch ALSP patients are referred to us
to discuss their disease prognosis and treatment possibilities, the ALSP
patients will be recruited during a hospital visit to the VUmc or AMC. Sample
collection from patients will take place during a period of 5 years (6 times in
total) at moment of venous blood sampling for standard clinical care. Reference
samples will be acquired via the mini donor bank in the UMC Utrecht.

The procedure includes collection of ±15ml extra venous blood at the moment of
venous blood sampling for standard clinical care. There is no direct benefit
for the patients; there is only benefit for the ALSP patient population by
increased knowledge. Risks and burdens of the study will be minimized by
collecting blood samples only during venous blood sampling in the context of
standard care.