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

Tama Dinur,Shoshana Revel-Vilk,Ari Zimran,Majdolen Istaiti,Arndt Rolfs,Ulrike Grittner,Michal Becker-Cohen,Claudia Cozma

doi:10.3390/ijms22147699

Abstract

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.

Highlights

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by partial deficiency of the lysosomal enzyme β-glucocerebrosidase, leading to accumulation of glucocerebroside in tissue macrophages, thereby mainly affecting the spleen, liver, and bone marrow [1]
For the neuronopathic forms, there is a significant diversity that may impact medical decisions related to the continuation of pregnancy or selection of therapy, investigational ones, as no specific treatment is currently available for types 2 and 3 [7]
In this longitudinal observational study, 135 patients (77, 57% female) with GD1 were on enzyme replacement therapy (ERT) at the first observation time point over a median period of 51 months (Table 1)

Summary

Introduction

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by partial deficiency of the lysosomal enzyme β-glucocerebrosidase, leading to accumulation of glucocerebroside in tissue macrophages, thereby mainly affecting the spleen, liver, and bone marrow [1]. The disease is pan-ethnic and has an estimated prevalence of 1:50,000– 100,000 in the general population, but with a predilection for Ashkenazi Jews, wherein 1:17 are carriers and about 1:800 is affected [2]. Gaucher disease has been traditionally divided into three clinical forms: type 1 (GD1), a chronic, non-neuronopathic form, defined by the absence of central nervous system (CNS). Many comorbidities impact the clinical features of GD, some of which are significantly more common in GD than in the general population, such as Parkinson’s disease and various hematological disorders [4]. For the neuronopathic forms, there is a significant diversity that may impact medical decisions related to the continuation of pregnancy or selection of therapy, investigational ones, as no specific treatment is currently available for types 2 and 3 [7]

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Discussion

Conclusion