Developing biomarkers to study drugs for neurodegenerative diseases

‘Biotech companies looking for a suitable target for inhibiting neurodegeneration often come up with compounds that affect lysosomal function,’ says Dr Philip Kremer, Research Director in Neurology. Lysosomes, small membrane-covered compartments within the cell, play a crucial role in the cell’s metabolism and ‘waste disposal’ processes. When lysosomes malfunction, defective proteins or other molecules accumulate in the cell. In brain cells, this accumulation likely plays a role in a variety of neurodegenerative diseases, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and various forms of dementia.

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Parkinson’s and similar diseases

CHDR has conducted several studies with such drugs in recent years. In one study, researchers investigated the efficacy of a compound that stimulates the activity of the lysosomal enzyme glucocerebrosidase. This study focused specifically on patients with a variant of the gene for this enzyme, who were selected through a large-scale screening of PD patients. Another recent study looked at a PD drug that inhibits the lysosomal enzyme LRRK2.

‘PD belongs to a group of diseases that we now know are associated with accumulation of so-called alpha-synuclein proteins,’ says Kremer. ‘Other synucleinopathies include Lewy body dementia and multiple system atrophy. With a group of biochemically related disorders like this, it’s possible that a drug will be developed that is effective in more than one disorder.’

In other neurodegenerative diseases, different proteins are involved. ALS, for example, is linked to aggregates of a protein known as TDP-43. The same protein plays a role in some patients with frontotemporal dementia. Meanwhile, in Alzheimer’s disease — the most common form of dementia — there is accumulation of beta amyloid and tau protein.

Biomarkers for lysosomal pathways

Researchers at CHDR are always on the hunt for new ways to study the pharmacodynamics of novel compounds in the early stages of clinical development. CNS compounds that directly affect neurophysiology can be studied using the NeuroCart® test battery. To study compounds that primarily influence cellular functions, however, the researchers need a proxy for brain cells.

In the Research & Development lab, Dr Matthijs Moerland and his colleagues are developing assays that target white blood cells, particularly peripheral blood mononuclear cells (PBMCs). These easily accessible cells contain an active lysosomal apparatus, offering a proxy to test the effects of new compounds for treating neurodegenerative diseases.

‘Which tests we need depends on the compound and the mechanism of action,’ says Moerland. ‘Sometimes you can see an immediate effect of an agent, and sometimes you have to stress the cells a bit first, for example with bacterial lipopolysaccharides (LPS). We’ve developed tests for different lysosomal pathways in recent years and we’re continuing to develop our cellular test battery. With these biomarkers, we can assess drug effects in the blood of healthy volunteers. Specifically, we can see if a drug does indeed affect the target pathway at the dose we administered.’

Kremer: ‘By also measuring drug concentrations in the cerebrospinal fluid, we can model the concentration in the target areas in the brain. Together, these measurements reveal pharmacodynamic action at the cellular level in healthy volunteers, as well as in early clinical studies with patients. This kind of qualitative and quantitative information is highly valuable for the further clinical development of a compound.’