Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease.

Renuka P Limgala,Ozlem Goker-Alpan

doi:10.3390/biom10040526

Abstract

Gaucher disease (GD) is caused by mutations in the GBA gene, leading to deficient activity of the lysosomal enzyme glucocerebrosidase. Among all the symptoms across various organ systems, bone disease is a major concern as it causes high morbidity and reduces quality of life. Enzyme replacement therapy (ERT) is the most accepted treatment; however, there are still unmet needs. As an alternative, substrate reduction therapy (SRT) was developed using glucosylceramide synthase inhibitors. In the current study, the effects of ERT vs. SRT were compared, particularly the immunological and bone remodeling aspects. GD subjects were divided into three cohorts based on their treatment at initial visit: ERT, SRT, and untreated (UT). Immunophenotyping showed no significant immune cell alterations between the cohorts. Expression of RANK/RANKL/Osteoprotegerin pathway components on immune cells and the secreted markers of bone turnover were analyzed. In the ERT cohort, no significant changes were observed in RANK, RANKL or serum biomarkers. RANKL on T lymphocytes, Osteopontin and MIP-1β decreased with SRT treatment indicating probable reduction in osteoclast activity. Other secreted factors, Osteocalcin and RANKL/Osteoprotegerin did not change with the treatment status. Insights from the study highlight personalized differences between subjects and possible use of RANK pathway components as markers for bone disease progression.

Highlights

Gaucher disease (GD) (OMIM ID: 230800) is the most prevalent lysosomal disorder, caused by pathogenic mutations in the GBA gene, leading to a deficient activity of the lysosomal enzyme β-glucocerebrosidase (GCase)
Since the hallmark of GD is the accumulation of sphingolipids including GL-1 and lyso GL-1, especially in the cells of monocyte/macrophage lineage, the effect of immune system modulation on bone development and remodeling is not trivial
It has been shown that certain GD patients continue to develop avascular necrosis (AVN) even after being on long-term Enzyme replacement therapy (ERT), especially if the treatment was delayed more than 2 y after diagnosis [21]

Summary

Introduction

Gaucher disease (GD) (OMIM ID: 230800) is the most prevalent lysosomal disorder, caused by pathogenic mutations in the GBA gene, leading to a deficient activity of the lysosomal enzyme β-glucocerebrosidase (GCase). The effects of the glycolipid accumulation are manifested in multiple organ systems, resulting in major signs and symptoms that include enlargement of the liver and spleen (hepatosplenomegaly), lung disease and skeletal abnormalities [1] Among all these symptoms, bone disease is a major matter of concern for physicians as it causes high morbidity and reduces quality of life. Structural complications can further be subclassified into (1) focal infarcts leading to avascular necrosis (osteonecrosis), sclerosis and osteolytic lesions, (2) generalized osteoporosis and osteopenia, which result in reduced bone density and frequent fractures, and (3) local manifestations that include structural deformities (Erlenmeyer flask deformities) and cortical thinning [2] Such extensive involvement of complications encompassing multiple facets of the skeletal system occurs in very few cases as the inherent pathology of a medical condition, but rather as a result of the response to external factors such as exposure to long-term corticosteroid medications, radiation therapy, organ transplants etc. Several immune cell subtypes including T/B lymphocytes and dendritic cells (DC) along with secreted factors participate in bone-immune system cross talk affecting osteoblast/osteoclast related bone remodeling [4,5]

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Conclusion