scholarly journals Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease

2021 ◽  
Author(s):  
Margarita Ivanova ◽  
Julia Dao ◽  
Neil Kasaci ◽  
Benjamin Adewale ◽  
Shaista Nazari ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Lines ◽  
Gaucher Disease ◽  
Molecular Mechanisms ◽  
Substrate Reduction Therapy ◽  
Mineral Density ◽  
Equal Distribution ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Mitochondrial Functions

AbstractGaucher disease (GD) is caused by the deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase), and the subsequent accumulation of its substrate, glucosylceramide substrate (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) lead to GCase misfolding and inhibiting the lysosome’s proper trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway.GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes the GC biosynthesis, reducing a GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density.The effects of EGT and ABX on GCase activity and autophagy-lysosomal pathway (ALP) were assessed in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. While both compounds enhanced GCase activity in control cells, an individualized response was observed in cells from patients with GD2-3 that varied with GBA mutations. EGT and AMB enhanced the formation of lysosomal/ late endosomal compartments and autophagy, and this effect was independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of the mitochondrial function by activating the mitochondrial membrane potential.These results suggest that EGT and ABX may have different molecular mechanisms of action, but both enhance GCase activity, improve autophagy-lysosome dynamics and mitochondrial functions.

scholarly journals Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0247211
Author(s):  
Margarita M. Ivanova ◽  
Julia Dao ◽  
Neil Kasaci ◽  
Benjamin Adewale ◽  
Shaista Nazari ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Lines ◽  
Gaucher Disease ◽  
Molecular Mechanisms ◽  
Substrate Reduction Therapy ◽  
Mineral Density ◽  
Equal Distribution ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Mitochondrial Functions

Gaucher disease (GD) is caused by deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase) and the subsequent accumulation of its substrate, glucosylceramide (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) cause GCase misfolding and inhibition of proper lysosomal trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway. GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no direct impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes GC biosynthesis, reducing GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density parallel with the improvement in hematological parameters. We assessed the effects of EGT and AMB on GCase activity and autophagy-lysosomal pathway (ALP) in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. We found that EGT, same as AMB, enhanced GCase activity in control cells and that an individualized response, that varied with GBA mutations, was observed in cells from patients with GD2-3. EGT and AMB enhanced the formation of lysosomal/late endosomal compartments and improved autophagy, independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of mitochondrial function by activating the mitochondrial membrane potential. These results demonstrate that EGT and AMB, with different molecular mechanisms of action, enhance GCase activity and improve autophagy-lysosome dynamics and mitochondrial functions.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

2008 ◽  
Vol 31 (6) ◽  
pp. 745-752 ◽  
Author(s):  
J. Cox-Brinkman ◽  
M. J. van Breemen ◽  
B. T. van Maldegem ◽  
L. Bour ◽  
W. E. Donker ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Disease Type ◽  
Substrate Reduction Therapy ◽  
Type Iii ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Potential Efficacy

Gaucher Disease

2016 ◽  
Author(s):  
Carla E.M. Hollak
Keyword(s):  
Bone Disease ◽  
Gaucher Disease ◽  
Severe Disease ◽  
Substrate Reduction Therapy ◽  
Disease Treatment ◽  
Enzyme Replacement ◽  
Rare Cancers ◽  
Substrate Reduction ◽  
Associated Conditions

Gaucher disease is frequently diagnosed in adulthood and may manifest at any age. Chronic neuronopathic forms are rarely seen but may come to the attention of the adult physician. Nonneuronopathic or type 1 disease is extremely variable. Main symptoms are cytopenia, hepatosplenomegaly and bone disease. The majority of patients diagnosed in adulthood present with thrombocytopenia and splenomegaly. In moderate to severe disease, treatment with intravenous enzyme replacement is highly effective. Substrate reduction therapy with miglustat or eliglustat is an oral alternative for some. Awareness of a number of severe complications and associated conditions, including irreversible bone disease, rare cancers and Parkinson's disease, is of importance.

Balanced Oral Substrate Reduction Therapy for Patients with Mild to Moderate Gaucher’s Disease: Initial Results in Clinical Practice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3820-3820
Author(s):  
Derralynn A. Hughes ◽  
Robert J. Baker ◽  
Linda Richfield ◽  
Alan Milligan ◽  
Rebecca Bruce ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Disease Activity ◽  
Gaucher Disease ◽  
Venous Access ◽  
Substrate Reduction Therapy ◽  
Haematological Parameters ◽  
Type I ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Serum Lysozyme

Abstract Gaucher Disease is a glycosphingolipid storage disorder resulting from deficiency of the enzyme glucocerebrosidase. Therapeutic modalities include enzyme replacement by infusion of recombinant glucocerebrosidase or reduction of substrate accumulation by inhibition of glucosyl ceramide synthetase. The Advisory Council to the European Working Group on Gaucher Disease (EWGGD) [1] consider that patients with type I GD who are unsuitable for enzyme replacement therapy (ERT) are eligible for oral substrate reduction therapy (SRT) with miglustat. We have 4 patients (3 male, 1 female, age range 23–81 years) who have commenced oral SRT with miglustat after being assessed as unsuitable for ERT. These patients all fulfilled criteria for mild to moderate Gaucher Disease having haemoglobin greater than 9g/dl, platelets greater than 50 x109/l and no evidence of progressive osseous disease on magnetic resonance imaging. Unsuitability for ERT was to due regular travel out side the United Kingdom or persistent difficulty with cannulation because of poor venous access or, in one case, a Parkinsonian tremor. The median duration of prior enzyme treatment was 7 years and the median current duration of SRT 5.75 months. One patient was splenectomised. Miglustat was initially commenced at 100mg od or b.i.d and the dose escalated to 100mg t.i.d over one to two months. Patients were monitored each month for changes in clinical state, haematological parameters and biomarkers of disease activity including chitotriosidase activity, angiotensin converting enzyme, acid phosphatase and serum lysozyme. Flatulence and diarrhea occurred in three patients after starting miglustat treatment but was ameliorated with temporary dose reduction, loperamide treatment, or introduction of a lactose-free diet. The patients clinical, neurological status and cognitive ability, assessed by the Mini-Mental State Examination, have remained stable since starting miglustat treatment. One patient has undergone incidental laparotomy resulting in suspension of oral therapy. No clinically significant changes in haematological parameters have been noted over the first six months of therapy. Markers of macrophage storage were initially elevated with mean increase in chitotriosidase of 87 +/− 168% at one month after the start of SRT. Levels then fell progressively and by 4 months there was a mean reduction in chitotriosidase of 3.75+/− 3.8% below baseline. Serum lysozyme and acid phosphatase and were similarly reduced by 28 +/−10% and 7.1 +/−10% after 3 and 4 months respectively. Our initial experience with 4 patients with type I GD and poor venous access, including the oldest patient for whom miglustat treatment has been reported, indicates that oral miglustat provides an effective alternative for patients unsuitable for ERT. Clinical and haematological parameters are stable and after 4 months of treatment improvement in biomarkers of disease activity is noted.

scholarly journals Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease

2003 ◽  
Vol 358 (1433) ◽  
pp. 955-960 ◽  
Author(s):  
Chris Moyses
Keyword(s):  
Gaucher Disease ◽  
Clinical Manifestations ◽  
Residual Activity ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Clinical Consequences ◽  
Type 1 Gaucher Disease

Glycosphingolipid (GSL) lysosomal storage disorders are inherited enzyme deficiencies that result in pathological lysosomal accumulation of glycolipids, with widespread clinical consequences. Type 1 Gaucher disease is the commonest of these; the deficient enzyme in this condition is glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, anaemia, recurrent infections and skeletal lesions. The condition can be treated with intravenous enzyme replacement therapy (ERT). Substrate reduction therapy is a new approach in which glycolipid accumulation is counteracted not by replacing the deficient enzyme but by reducing the substrate level to better balance residual activity of the deficient enzyme. Miglustat is an inhibitor of glucosylceramide synthase, a key enzyme in GSL synthesis. Oral administration of miglustat to patients with type 1 Gaucher disease attenuates the synthesis of glucocerebroside, the substrate of the deficient glucocerebrosidase. In the first clinical study, patients with type 1 Gaucher disease who had enlargement of the liver or spleen and (if present) the spleen at baseline received 12 months treatment with oral miglustat. There were mean decreases in liver and spleen volumes of 12% (7.9–16.4, p < 0.001) and 19% (14.3–23.7, p < 0.001), respectively. Mean haemoglobin increased by 0.26 g dl −1 (−0.5−0.57, not statistically significant) and platelet count by 8.3 × 10 9 l −1 (1.9–14.7, p = 0.014).

Enzyme replacement and substrate reduction therapy for Gaucher disease

2013 ◽  
Author(s):  
Elad Shemesh ◽  
Laura Deroma ◽  
Bruno Bembi ◽  
Patrick Deegan ◽  
Carla Hollak ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Substrate Reduction Therapy ◽  
Enzyme Replacement ◽  
Substrate Reduction
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