Gaucher treatment doesn’t normalize key biomarker levels
Study finds lyso-Gb1 levels fall with DMT use, but remain above normal range
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Available disease-modifying therapies (DMTs) for Gaucher disease can decrease the levels of lyso-Gb1, a biomarker of disease burden, but levels remain significantly above the normal range in treated patients, a study found.
“We speculate that the persistently increased lyso-Gb1 levels may have been driven by underlying mechanisms, such as chronic inflammation …, that are not completely reversed by DMTs,” the researchers wrote.
The study, “Gaucher Disease—Correlation of Lyso-Gb1 with Haematology and Biochemical Parameters,” was published in the journal Metabolites.
Gaucher disease is caused by mutations in the GBA1 gene that result in a defective or missing glucocerebrosidase, an enzyme that helps to degrade the fatty molecule glucocerebroside (Gb1) into smaller components that cells can reuse. When GCase is missing or not functioning properly, Gb1 accumulates inside cells, which drives disease symptoms. The spleen, liver, and bones are primarily affected in Gaucher, but up to 10% of patients may also experience neurological symptoms.
Researchers have discovered in recent years that measuring levels of lyso-Gb1, a metabolite of Gb1 that also accumulates in Gaucher, could aid in Gaucher diagnosis and monitoring treatment responses. Higher lyso-Gb1 levels have also been found to correlate with more severe disease. However, there’s limited data on how this biomarker is affected by treatment and other clinical and demographic factors.
Analyzing levels in treated patients
To gain more insight, a research team in the U.K. examined lyso-Gb1 levels in 100 adult Gaucher patients. All had at least one lyso-Gb1 measurement, and nearly all (93%) were receiving treatment. Most (73%) were on enzyme replacement therapy (ERT), while the remaining 27% were on substrate reduction therapy (SRT).
As expected, the median lyso-Gb1 values were significantly higher in treatment-naïve patients than in those receiving DMTs, but lyso-Gb1 levels remained above the normal range even in treated patients.
The team then assessed whether lyso-Gb1 levels varied in the treated group by sex, Gaucher disease type, mutation, treatment type and dose, spleen status, and other Gaucher biomarkers.
No statistically significant differences in lyso-Gb1 levels were observed between men and women, across different ERT doses, or between patients on ERT or SRT. However, patients who carried two copies of a GBA1 mutation called N370S, who generally have a milder disease form, showed significantly lower lyso-Gb1 levels than those with one N370S mutation and a different mutation in the second copy of the gene.
Patients treated for at least 15 years also had significantly higher lyso-Gb1 levels than those treated for less time. Those who had their spleens surgically removed (splenectomy) also exhibited significantly higher lyso-Gb1 levels than those with intact spleens.
In a subgroup of 50 patients with two lyso-Gb1 measurements, levels showed a slight overall decrease over a median follow-up of about three years. The greatest reductions were observed in women, in patients with Gaucher type 3, and in those carrying the L444P mutation.
Treatment-naïve patients who started on medication also showed significantly greater reduction in lyso-Gb1 levels over time compared with treated patients.
“Lyso-Gb1 concentrations are reflective of disease severity and treatment status, with naive patients showing greater lyso-Gb1 values [before treatment] and the most pronounced reduction after treatment initiation,” the researchers concluded. “Determining the reasons for non-normalisation of lyso-Gb1 values in the context of clinical stability requires further investigations.”
