Surrogate markers for lysosomal storage

Enzyme replacement therapy (ERT) for lysosomal storage disorders (LSDs) is safe and effective treatment. It was first developed for Gaucher disease (GD), a disorder in which the bone marrow and the tissue macrophages derived from it play a central role in its pathogenesis. Currently, ERT is being developed for other LSDs following the blueprint developed for GD. This approach uses receptor-mediated endocytosis of glycoprotein lysosomes/enzymes by naturally occurring lectins.¹  Successful clinical trials resulted in new enzyme therapies becoming available a few months ago for patients with Fabry disease and mucopoly-saccharidoses I.

The development of enzyme replacement therapy for GD prompted several research groups to identify biochemical markers to allow the clinician to monitor the disease and make the appropriate dosing decisions. Currently, chitotriosidase, angiotensin-converting enzyme, and tartrate-resistant acid phosphatase are the most commonly used surrogate markers to monitor disease progression and response to ERT in GD patients. Chitotriosidase is a good marker for this purpose because it is specific for GD and shows a dramatic response after initiation of therapy, decreasing an average of 50% after the first 3 months of treatment and by 80% after one year. The usefulness of chitotriosidase is limited to a small degree by a recessively inherited 24-bp deletion that is present in 5% to 6% of the population.²  Treating physicians would welcome surrogate markers that could confirm the value of chitotriosidase and be universally applicable in the evaluation of the disease severity and the monitoring of treatment.

Boot and colleagues (page 33) have found that CCL18 is an interesting marker that can be very useful in this regard.

The use of surface-enhanced laser desorption/ionization–time of flight (SELDI-TOF) mass spectrometry is important in identifying potential previously unknown factors related to GD, regardless of its severity. The technique is currently used with success to identify biomarkers of disease activity in several research fields, including cancer biology. It was applied to GD to uncover the chemokine CCL18 as a marker. The correlation between the reductions of plasma CCL18 and the other markers studied in the report demonstrates CCL18 to be a reliable marker to monitor responses to treatment. What makes this marker a particularly promising approach for monitoring GD therapy is that, besides presenting similar response patterns to ERT to those observed with chitotriosidase, it is closely correlated with experiments in the lumbar bone marrow fat fraction. This provides an important adjunct in documenting the skeletal response to ERT.

This interesting report raises many questions regarding possible interferences with the utility of CCL18 as a biomarker. Pathologic entities such as rheumatoid arthritis and other inflammatory conditions that affect bones and joints can be concurrent with GD.³  CCL18 has not yet been studied in these. Although CCL18 has been noted to be increased in unrelated pathologic conditions,⁴  the clinical manifestations of these diseases make it easy to distinguish between them and not diminish the value of CCL18.

This study provides new insight into the pathophysiology of GD and to the association of CCL18 with the phenotypic expression of the disease. This advance is a first step in further research on this chemokine. The fact that commercially available products can be used to determine the levels of this chemokine facilitates experimental and clinical applications. The report also demonstrates the feasibility of using SELDI-TOF mass spectrometry to identify surrogate markers in other lysosomal storage diseases that allow the follow-up of patients for whom enzyme therapy has been made available in the last few months.