Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement

Elstein, Deborah; Dweck, Altoon; Attias, Denise; Hadas‐Halpern, Irith; Zevin, Shoshana; Altarescu, Gheona; Aerts, Johannes M. F. G.; Weely, Sonja van; Zimran, Ari

doi:10.1182/blood-2007-02-075960

Cited by 109 publications

(88 citation statements)

References 33 publications

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“…38 In addition, another well-tolerated inhibitor of GSLs biosynthesis (Genz-112638) is presently being developed as oral therapy for Gaucher disease. 39 Our investigation indicates that additional studies are warranted regarding the use of GSL biosynthesis inhibitors for cardioprotective therapy.…”

Section: Bietrix Et Almentioning

confidence: 99%

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Bietrix

Lombardo

Roomen

et al. 2010

ATVB

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Objective-The iminosugar N-(5Ј-adamantane-1Ј-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase catalyzing glycosphingolipid (GSL) biosynthesis, ameliorates diabetes and reduces liver steatosis in ob/ob mice. Because an accumulation of sphingolipids, including sphingomyelin and GSLs, has been reported in atherosclerotic lesions in animal models and in humans, the objective of this study was to determine whether AMP-DNM also exerts beneficial effects on the development of atherosclerosis. Methods and Results-APOE*3 Leiden mice, maintained on a high-cholesterol diet, were treated for up to 18 weeks with AMP-DNM. The iminosugar prevented hyperlipidemia, generated a less atherogenic lipid profile, and induced a dramatic reduction in the development of atherosclerotic lesions. At the highest dose, no lesions were detectable. The effect of AMP-DNM was associated with a decrease in liver cholesterol, an increase in bile secretion, and enhanced excretion of cholesterol in the feces. Similar effects of AMP-DNM were observed in mice deficient for the low-density lipoprotein receptor. Conclusion-By

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Section: Bietrix Et Almentioning

confidence: 99%

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Bietrix

Lombardo

Roomen

et al. 2010

ATVB

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“…3 This frequently called substrate reduction therapy is now widely applied in the clinic as an alternative for enzyme replacement therapy, in which recombinant GBA1 is administered to the patients. [4][5][6] Glucosylceramide is also the starting point in the biosynthesis of a wide variety of glycosphingolipids, of which many are found as the storage material in lysosomal glycolipid storage disorders related to Gaucher disease (Fabry, Tay-Sachs, etc.) and in which a specific lysosomal glycohydrolase is genetically impaired.…”

mentioning

confidence: 99%

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Ghisaidoobe

Bikker

Bruijn

et al. 2010

ACS Med. Chem. Lett.

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Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated L-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.

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“…The punch-line of this survey should therefore be that we now need to get some patients off this particular merry-go-round and offer drug-free periods with a wait-and-see follow-up algorithm. Patients with no measurable remaining disease [17] (e.g., near-normalization of hemoglobin, platelets, and liver and spleen volumes, as the 195 patients presented here), may all be excellent candidates.…”

mentioning

confidence: 94%

Using the International Gaucher Disease Registry data: Can we devise a virtuous circle for treated patients?

Elstein

Zimran

2008

American J Hematol

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Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement

Cited by 109 publications

References 33 publications

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Using the International Gaucher Disease Registry data: Can we devise a virtuous circle for treated patients?

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