Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project

Giraldo, Pilar; Andrade‐Campos, Marcio; Alfonso, Pilar; Irún, Pilar; Atutxa, Koldo; Acedo, Antonio; Bárez, Abelardo; Blanes, Margarita; Diaz-Morant, Vicente; Fernández-Galán, MA; Franco, Rafael; Gil-Cortés, Cristina; Giner, Vicente; Ibáñez, Angela; Latre, Paz; Loyola, Ines; Luño, Elisa; Hernández-Martin, Roberto; Medrano-Engay, Blanca; Puerta, Jose Manuel; Roig, Inmaculada; Serna, Javier de la; Salamero, Olga; Villalón, Lucı́a; Pocovı́, Miguel

doi:10.1016/j.bcmd.2016.10.017

Cited by 25 publications

(18 citation statements)

References 29 publications

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“…These included diarrhea, weight loss, tremor, and peripheral neuropathy. As a result, 49 of 115 patients discontinued use of miglustat after experiencing such side effects [120–122].…”

Section: Therapeutic Treatment Goals For Gdmentioning

confidence: 99%

Recent advances in the diagnosis and management of Gaucher disease

Gary

Ryan

Steward

et al. 2018

Expert Review of Endocrinology & Metabolism

111

107

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Gaucher disease, the autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase, is associated with wide phenotypic diversity including non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms. Overlap between types can render definitive diagnoses difficult. However, differentiating between the different phenotypes is essential due to the vast differences in clinical outcomes and response to therapy. Genotypic information is helpful, but cannot always be used to make clinical predictions. Current treatments for Gaucher disease, including enzyme replacement therapy and substrate reduction therapy, can reverse many of the non-neurological manifestations, but these therapies must be administered continually and are extremely costly. Areas covered: We reviewed the literature concerning the varied clinical presentations of Gaucher disease throughout the lifetime, along with treatment options, management goals, and current and future research challenges. A PubMed literature search was performed for relevant publications between 1991 to January 2018. Expert commentary: Interest and research in the field of Gaucher disease is rapidly expanding. However, significant barriers remain in our ability to predict phenotype, assess disease progression using objective biomarkers, and determine optimal treatment strategy on an individual basis. As the field grows, we anticipate identification of genetic modifiers, new biomarkers, and small-molecule chaperone therapies, which may improve patient quality of life.

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“…These included diarrhea, weight loss, tremor, and peripheral neuropathy. As a result, 49 of 115 patients discontinued use of miglustat after experiencing such side effects [120–122].…”

Section: Therapeutic Treatment Goals For Gdmentioning

confidence: 99%

Recent advances in the diagnosis and management of Gaucher disease

Gary

Ryan

Steward

et al. 2018

Expert Review of Endocrinology & Metabolism

111

107

View full text Add to dashboard Cite

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“…The iminosugar Miglustat (N-butyl-deoxynojirimycin), a registered oral agent to treat mild type 1 GD, markedly inhibits GBA2 activity at the administered dose (3 times 100 mg daily) (47). A very large number of type 1 GD patients have been treated with Miglustat for more than a decade without major side effects except for intestinal complaints due to inhibition of intestinal glycosidases (63). Apparently, in these individuals GBA2 inhibition has no overt detrimental consequences.…”

Section: Downloaded Frommentioning

confidence: 99%

Role of μ-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish

Lelieveld¹,

Mirzaian²,

Kuo³

et al. 2019

Journal of Lipid Research

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β-glucosidases (GBA1 [glucocerebrosidase], GBA2, and GBA3) are ubiquitous, essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes Gaucher disease (GD), a lysosomal storage disorder characterized by lysosomal accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). GBA1 and GBA2 also may transfer glucose from GlcCer to cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed to clarify the role of zebrafish Gba2 in glycosphingolipid metabolism during Gba1 deficiency in zebrafish (Danio rerio), which are able to survive total Gba1 deficiency. We developed Gba1 and Gba2 zebrafish knockouts (gba1-/and gba2-/-, respectively) using CRISPR/Cas9, modulated glucosidases genetically and pharmacologically, studied GlcCer metabolism in individual larvae, and explored the feasibility of pharmacologic or genetic interventions. Activity-based probes and quantification of relevant glycolipid metabolites confirmed enzyme deficiency. GlcSph increased in gba1-/larvae (0.09 pmol/fish) but did not increase more in gba1-/-:gba2-/larvae. GlcCer was comparable in gba1-/and wild-type (WT) larvae but increased in gba2-/and gba1-/-:gba2-/larvae. Independent of Gba1 status, GlcChol was low in all gba2-/larvae (0.05 vs. 0.18. pmol/fish in WT). Pharmacologic inactivation of zebrafish Gba1 comparably increased GlcSph. Inhibition of glucosylceramide synthase in Gba1-deficient larvae reduced GlcCer and GlcSph, and concomitant inhibition of glucosylceramide synthase and Gba2 with iminosugars also reduced excessive GlcChol. Finally, overexpression of human GBA1 and injection of recombinant GBA1 both decreased GlcSph. We determined that zebrafish larvae offer an attractive model to study glucosidase actions in glycosphingolipid metabolism in vivo, and we identified distinguishing characteristics of zebrafish Gba2 deficiency.

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“…Miglustat has previously been shown to be an effective long-term maintenance treatment for core hematologic and visceral symptoms in GD [ 13 , 16 ], and studies suggest that it can produce significant improvements in bone status, reducing bone pain as early as 6 months after treatment start [ 15 ]. In both cases presented here, miglustat administered as monotherapy demonstrated satisfactory maintenance of core GD disease parameters in patients stabilized on ERT, as has been reported previously [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Short-term clinical trials and long-term, open-label extension studies demonstrated the efficacy and safety of the first approved oral SRT, miglustat (Zavesca®, N-butyldeoxynojirimycin [NB-DNJ], Actelion Pharmaceuticals, Basel, Switzerland), in treating core hematologic and visceral symptoms of GD [ 11 – 13 ]. A long-term study has further shown that miglustat can be used as a maintenance therapy in patients with stable GD1 switched from previous ERT [ 14 ], and the effects of miglustat in improving bone pain and bone mineral density (BMD) over 2–12 years have been reported in other studies [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports

Amato

Patterson

2018

J Med Case Reports

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BackgroundIntravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods.Case presentationWe report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy.ConclusionWhile the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy and enzyme replacement therapy, the current case reports demonstrate that judicious use of combination therapy may be of benefit in some cases.

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Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project

Cited by 25 publications

References 29 publications

Recent advances in the diagnosis and management of Gaucher disease

Recent advances in the diagnosis and management of Gaucher disease

Role of μ-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish

Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports

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