Components of the RANK pathway — a biological pathway that acts as a bridge between the immune and skeletal systems — may be used as markers of bone disease progression in patients with Gaucher disease, a study says.
The study, “Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease,” was published in the journal Biomolecules.
Gaucher disease is caused by a mutation in the GBA gene, which compromises the production of beta-glucocerebrosidase, an enzyme responsible for breaking down a fatty substance called glucocerebroside. As a result, glucocerebroside gradually builds up inside immune cells called macrophages, which then become Gaucher cells that infiltrate different organs and tissues.
Among all the different manifestations of Gaucher, bone disease is one of the major concerns due to its negative impact on patients’ quality of life.
Bone remodeling, which results from the balance between bone formation and destruction, is influenced by substances produced by certain types of immune cells.
Due to its close relationship with the skeletal system — partly mediated through the RANK signaling cascade — the immune system is also thought to be involved in bone disease associated with Gaucher.
Enzyme replacement therapy (ERT) is currently considered the gold standard treatment for Gaucher, but fails to target some aspects of the disease. For this reason, alternative treatments, including substrate reduction therapy (SRT), are being explored.
ERTs are based on the principle of providing patients with artificial enzymes meant to replace those they are missing. In turn, SRTs seek to prevent the body from producing the toxic substances that accumulate inside cells. In the case of Gaucher, this can be achieved by using blockers of glucosylceramide synthase, the enzyme that normally produces glucocerebroside.
In the study (NCT02605603), investigators at the Lysosomal and Rare Disorders Research and Treatment Center compared the effects of ERT and SRT on immunological and bone remodeling aspects in patients with Gaucher.
The study included 32 patients, who were divided into three groups — ERT, SRT, or untreated — based on the treatment they were receiving at their first study visit.
Specifically, the ERT group included 14 patients who were being treated with VPRIV (velaglucerase alfa) or Cerezyme (imiglucerase) for a long period of time. The SRT group included 10 patients who switched to Cerdelga (eliglustat) during their first study visit, and the untreated group included eight patients who were not receiving therapy or had interrupted treatment.
All patients were evaluated in three study visits, which took place over the course of 12 to 18 months. During each visit, investigators collected blood samples that were used to assess the levels of immune cells, immune markers, and biomarkers of bone remodeling.
At enrollment, 72% of the patients had bone alterations that were visible on radiographs, and 59% reported bone pain.
Analyses found no significant differences in the levels of immune cells between the three patient groups, suggesting that “treatment differences did not influence overall immune cell subsets in a significant manner.”
No significant changes in RANKL, its protein receptor RANK, or in any other blood biomarkers were found over the three study visits in patients receiving ERT.
However, the levels of RANKL on the surface of immune T-cells, as well as the levels of osteopontin (a bone remodeling biomarker) and MIP-1 beta (a bone disease biomarker) decreased over time in patients who switched to SRT.
According to the authors, these findings may indicate that patients receiving SRT are probably experiencing a “reduction in osteoclast activity that could result in lower bone resorption.” Notably, osteoclasts are specialized cells responsible for destroying and re-absorbing bone.
Despite its short duration, the results “highlight personalized differences between subjects with different treatment modalities,” wrote the investigators, who also suggested the “possible use of RANK pathway components as markers for bone disease progression” in Gaucher patients.