Rational use of substrate reduction therapy and enzyme replacement therapy in patients with type I Gaucher disease (Uso racional de los tratamientos por inhibición de sustrato y enzimático sustitutivo en pacientes con enfermedad de Gaucher tipo I)

Abstract Gaucher disease (GD) is caused by a deficiency of the lysosomal enzyme acid β-glucosidase (GC) leading to accumulation of glucosylceramide within the macrophages of the reticuloendothelial systems. Plasma of GD patients contains low levels of total cholesterol, LDL-cholesterol and HDL-cholesterol. Enzyme replacement therapy (ERT) with imiglucerase and Substrate Reduction Therapy (SRT) with miglustat restores the haemoglobin levels, platelet counts and organomegalies. Previously we have demonstrated that ERT had significant effects on the concentration and metabolism of plasma lipoproteins. However, the effects of SRT on plasma lipid and other atherogenic profiles of GD patients have not been explored. We report the results of long term (36 months) SRT on plasma lipoprotein concentrations in 26 (11 men and 15 women) GD patients. Mean age of patients was 51 (SD ±20.7; range 22–74) years. Ten patients were therapy-naïve to SRT and 16 switched from previous enzyme replacement therapy (ERT). All patients received 100 mg of Miglustat t.i.d with recommendations of a low hydrocarbonate diet in the first weeks. Total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-C), Apolipoproteins (Apo AI, ApoB and Lp(a)), CRP, MPI1b, CCL18 concentrations and chitotriosidase activity were measured before (baseline) and after 12, 24 and 36 months of follow-up. Treatment resulted in a significant increases in HDL-c concentration in naïve patients during the first 24 months (p<0.02) on therapy and it is maintain till 36 months. The same trend was observed in HDL-cholesterol in switch patient but with a less increase that in naïve patients. TC increase slightly in switch (p<0.05) and naïve (p<0.04) patients after 24 and 36 months of treatment respectively. No significant changes in LDL-c during treatment were observed in both switch and naïve patient. In naïve patients, TG, Lp(a) and CRP concentrations, as well as the atherogenic index TC/HDL-c decreased significantly in patients after 24 months therapy and no changes were observed in switch patients. Our results indicate that miglustat treatment have an apparent beneficial effects on plasma lipid, lipoprotein and CRP concentrations resulting in an apparently less atherogenic lipid profile in GD patients. However further studies will be required to determine the impact of miglustat treatment on the risk of coronary heart disease.

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Impact of Long-Term Enzyme Replacement Therapy on Glucosylsphingosine (Lyso-Gb1) Values in Patients with Type 1 Gaucher Disease: Statistical Models for Comparing Three Enzymatic Formulations

International Journal of Molecular Sciences ◽

10.3390/ijms22147699 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7699

Author(s):

Tama Dinur ◽

Ulrike Grittner ◽

Shoshana Revel-Vilk ◽

Michal Becker-Cohen ◽

Majdolen Istaiti ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Standard Of Care ◽

Repeated Measurements ◽

Substrate Reduction Therapy ◽

Compound Heterozygous ◽

Type I ◽

Enzyme Replacement ◽

The Impact

For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker). A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT (imiglucerase (n = 41, 30.4%), taliglucerase alfa (n = 21, 15.6%) and velaglucerase alfa (n = 73, 54.1%)), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index (SSI; mild: <7; severe: ≥7). Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions.

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

Biomolecules ◽

10.3390/biom10040526 ◽

2020 ◽

Vol 10 (4) ◽

pp. 526 ◽

Cited By ~ 1

Author(s):

Renuka P. Limgala ◽

Ozlem Goker-Alpan

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Bone Disease ◽

Gaucher Disease ◽

Immune Cell ◽

Substrate Reduction Therapy ◽

High Morbidity ◽

Enzyme Replacement ◽

Substrate Reduction ◽

Organ Systems

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.

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