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The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged ≥18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of six; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28. Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference −8·8%; 95% CI −17·6 to 4·2). The lower bound of the 95% CI of −17·6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. Genzyme, a Sanofi company.

Background Dyslipidemia in Gaucher disease includes reduced total, low-density lipoprotein (LDL)-, and high-density lipoprotein (HDL)-cholesterol (C). No prospective analysis of lipid profile changes in treatment-naïve patients under enzyme replacement therapy (ERT) is available. Methods We analyzed lipid profile changes during ERT in a prospective controlled manner. Twelve treatment-naïve patients, Gaucher disease type 1 (GD1), 29.5 ± 12.9 years, 4M/8F. Diagnosis was made by enzymatic measurement and mutational analysis. Total-, LDL-, and HDL-C, triglycerides (TG), and LDL subfractions were assessed before the start of ERT with imiglucerase and biannually for 3 years. Patients were matched with healthy controls before and after 3 years of ERT. Results At baseline, we found severely reduced HDL-C concentrations (23.6 ± 5.4 mg/dl) and enhanced LDL/HDL ratios (3.1 ± 0.7). HDL-C increased after 6 months (29.2 ± 5.7, p  = 0.023), LDL/HDL ratio decreased after 30 months (2.5 ± 0.5, p  = 0.039). TG, even not consistently enhanced at baseline (128 ± 31.3 mg/dl), yet higher than in controls ( p  < 0.001), decreased after 18 months, being comparable with controls after 3 years of ERT. Small, dense LDL (mg/dl) increased continuously without significant difference to controls. After 3 years of ERT, only reduced HDL-C concentrations persisted as a potentially atherogenic alteration; however, mean concentrations markedly improved (42.9 ± 8.3 mg/dl, p  < 0.001). Lipid parameters correlated with six markers of disease severity. Conclusions This is the first prospective controlled study regarding lipid profile dynamics during ERT (glucocerebrosidase) in initially treatment-naïve GD1 patients. The most important changes were reduced HDL-C and enhanced LDL/HDL ratio. Their dynamics during ERT and correlations with markers of disease activity suggest that they can be considered markers of disease severity and follow-up in Gaucher patients under treatment.

Gaucher's disease continues to be a model for applications of molecular medicine to clinical delineation, diagnosis, and treatment. Analyses of several thousand affected individuals have broadened the range of the pan-ethnic disease variants, provided initial genotype and phenotype correlations, and established the effectiveness of enzyme therapy. Large numbers of affected individuals worldwide have provided insight into the effect of disease variation related to ethnic origin, prognosis, and outcome. The ability to safely and effectively use enzyme therapy to inhibit or reverse visceral-disease progression and involvement has provided impetus for design of new enzyme therapies, and creation of substrate depletion and pharmacological chaperone strategies. Such innovations could provide interventions that are effective for neuronopathic variants and, potentially, could be more cost effective than other treatments. These developments are novel, clinically important, advancements for patients with other lysosomal storage diseases and genetic diseases.

The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.

Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing. ClinicalTrials.gov NCT00258778.

In 2004, a study of 57 brains from individuals with Parkinson's disease was the first to show that heterozygous GBA1 variants could increase the risk of developing Parkinson's disease.1 Since then, other studies have shown the role of GBA1 variants in different Parkinson's disease populations.2 Additionally, efforts to study the cellular mechanisms underlying the association with GBA1 have generated different hypotheses on how gene variants might lead to Parkinson's disease. Glucosylceramide can interact with α-synuclein and increase its accumulation, and α-synuclein can then interact with glucocerebrosidase and prevent it from reaching the lysosome, creating a detrimental positive feedback loop.3 On the basis of these and similar data, researchers in the field hypothesised that reducing glucosylceramide concentrations by inhibition of glucosylceramide synthase could be a therapeutic approach for GBA1-associated Parkinson's disease. [...]glucosylceramide synthase inhibition was shown to reduce α-synuclein accumulation and signs of Parkinson's disease in two preclinical mouse models.4 Venglustat is a glucosylceramide synthase inhibitor that was tested in a phase 1 trial, with positive results.5 In The Lancet Neurology, Nir Giladi and colleagues report phase 2 results of venglustat in the MOVES-PD trial for people with GBA1-associated Parkinson's disease.6 Unfortunately, glucosylceramide synthase inhibition had a negative effect; individuals who received venglustat had markedly reduced glucosylceramide concentrations, yet their symptoms worsened more quickly than did those of people who received placebo.

Mutations of GBA1 , the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. Previously, we have shown that early treatment with glucocerebrosidase can modulate α-synuclein aggregation in a presymptomatic mouse model of Gaucher-related synucleinopathy (Gba1 ᴰ⁴⁰⁹ⱽ/ᴰ⁴⁰⁹ⱽ) and ameliorate the associated cognitive deficit. To probe this link further, we have now evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of symptomatic Gba1 ᴰ⁴⁰⁹ⱽ/ᴰ⁴⁰⁹ⱽ mice and in a transgenic mouse model overexpressing A53T α-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNS of symptomatic Gba1 ᴰ⁴⁰⁹ⱽ/ᴰ⁴⁰⁹ⱽ mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin, tau, and proteinase K-resistant α-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1 ᴰ⁴⁰⁹ⱽ/ᴰ⁴⁰⁹ⱽ mice (starting at 4 or 12 mo of age) also reversed their cognitive impairment when examined using a novel object recognition test. Correspondingly, overexpression of glucocerebrosidase in the CNS of A53T α-synuclein mice reduced the levels of soluble α-synuclein, suggesting that increasing the glycosidase activity can modulate α-synuclein processing and may modulate the progression of α-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1 -related and non- GBA1 –associated synucleinopathies, including PD.

Gaucher disease (GD) is an autosomal recessive disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase (GCase). Although enzyme replacement therapy (ERT) remains the standard of care for non-neuropathic GD patients, its high cost significantly limits accessibility. To enhance production efficiency, we developed a lentiviral system encoding a codon-optimized GCase gene driven by the human elongation factor 1a (hEF1α) promoter for stable production in human cell lines. A functional lentiviral vector, LV_EF1α_GBA_Opt, was generated at a titer of 7.88 × 108 LV particles/mL as determined by qPCR. Six transduction cycles were performed at a multiplicity of infection of 30–50. The transduced heterogeneous human cell population showed GCase-specific activity of 307.5 ± 53.49 nmol/mg protein/h, which represents a 3.21-fold increase compared to wild-type 293FT cells (95.58 ± 16.5 nmol/mg protein/h). Following single-cell cloning, two clones showed specific activity of 763.8 ± 135.1 and 752.0 ± 152.1 nmol/mg/h (clones 15 and 16, respectively). These results show that codon optimization, a lentiviral delivery system, and clonal selection together enable the establishment of stable human cell lines capable of producing high levels of biologically active, synthetic recombinant GCase in vitro. Further studies are warranted for the functional validation in GD patient-derived fibroblasts and animal models.

Background Fabry disease and Gaucher disease are rare genetic disorders characterized by defective degradation of glycosphingolipids caused by enzymatic deficiencies in α–galactosidase A and β–glucocerebrosidase, respectively, and often require life-long treatment. Treatment options for these disorders include replacing the deficient enzymes via enzyme replacement therapy (ERT). Agalsidase alfa for Fabry disease and velaglucerase alfa for Gaucher disease are two ERT options with demonstrated efficacy, safety, and tolerability. ERT infusions administered by a health care provider (HCP) in the clinic/hospital, or at the patient’s home are considered HCP-supported infusions. Self-administration of ERT (by patient, partner, relative, or caregiver) is optional in patients who tolerate the HCP-supported infusions at home and have a suitable home environment. This analysis explored the safety profiles of self-administered agalsidase alfa (202 patients) and velaglucerase alfa (30 patients) versus HCP-supported infusions using data from the Fabry Outcome Survey (FOS) and Gaucher Outcome Survey (GOS) registries. Results The frequency of infusion-related reactions (IRRs) adverse events (AEs) recorded in the two registries was lower in patients self-administering (FOS: 4.5%, GOS: 0%) versus patients receiving HCP-supported infusions (FOS: 13.6%, GOS: 1.6%). In the FOS registry, AE rates per 100 patient-years (100PY) of follow-up were similar between the self-administration (7.99) and HCP-supported infusion (6.78) groups. In patients self-administering agalsidase alfa, cardiac disorders were the most frequently reported AEs (19 [9.4%] patients) and serious AEs (12 [5.9%]) and gastrointestinal disorders were the most frequently reported IRRs (3 [1.5%]). In the GOS registry, AE rates per 100PY were similar between self-administration (4.97) and HCP-supported infusion (4.67) groups. In patients self-administering velaglucerase alfa, skin and subcutaneous disorders (4 [13.3%]) and infections and infestations (2 [6.7%]) were the most reported AEs and serious AEs, respectively, and no IRRs were reported. Conclusions These findings suggest that self-administration of agalsidase alfa or velaglucerase alfa infusions are not associated with additional safety risks compared with HCP-supported infusions and are a suitable option for qualifying patients. Further research is warranted to support these findings and to explore further the long-term safety and efficacy of ERT self-administration. FOS trial registration: ClinicalTrials.gov, NCT03289065. Registered 01 April 2001, https://clinicaltrials.gov/study/NCT03289065 . GOS trial registration: ClinicalTrials.gov, NCT03291223. Registered 27 July 2010, https://classic.clinicaltrials.gov/ct2/show/NCT03291223 .

The major cellular clearance pathway for organelle and unwanted proteins is the autophagy-lysosome pathway (ALP). Lysosomes not only house proteolytic enzymes, but also traffic organelles, sense nutrients, and repair mitochondria. Mitophagy is initiated by damaged mitochondria, which is ultimately degraded by the ALP to compensate for ATP loss. While both systems are dynamic and respond to continuous cellular stressors, most studies are derived from animal models or cell based systems, which do not provide complete real time data about cellular processes involved in the progression of lysosomal storage diseases in patients. Gaucher and Fabry diseases are rare sphingolipid disorders due to the deficiency of the lysosomal enzymes; glucocerebrosidase and α-galactosidase A with resultant lysosomal dysfunction. Little is known about ALP pathology and mitochondrial function in patients with Gaucher and Fabry diseases, and the effects of enzyme replacement therapy (ERT). Studying blood mononuclear cells (PBMCs) from patients, we provide in vivo evidence, that regulation of ALP is defective. In PBMCs derived from Gaucher patients, we report a decreased number of autophagic vacuoles with increased cytoplasmic localization of LC3A/B, accompanied by lysosome accumulation. For both Gaucher and Fabry diseases, the level of the autophagy marker, Beclin1, was elevated and ubiquitin binding protein, SQSTM1/p62, was decreased. mTOR inhibition did not activate autophagy and led to ATP inhibition in PBMCs. Lysosomal abnormalities, independent of the type of the accumulated substrate suppress not only autophagy, but also mitochondrial function and mTOR signaling pathways. ERT partially restored ALP function, LC3-II accumulation and decreased LC3-I/LC3-II ratios. Levels of lysosomal (LAMP1), autophagy (LC3), and mitochondrial markers, (Tfam), normalized after ERT infusion. In conclusion, there is mTOR pathway dysfunction in sphingolipidoses, as observed in both PBMCs derived from patients with Gaucher and Fabry diseases, which leads to impaired autophagy and mitochondrial stress. ERT partially improves ALP function.