Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis

Biochemical and Molecular Chitotriosidase Profiles in Patients with Gaucher Disease Type 1 in Minas Gerais, Brazil: New Mutation in CHIT1 Gene

“…The parameter most frequently employed to monitor effectiveness of this therapeutic intervention is the activity of chitotriosidase (ChT) (Cox et al 2000;Hollak et al 1994Hollak et al , 2001Mistry and Abrahamov 1997), a chitinase encoded by the chitotriosidase gene (CHIT1; MIM 600031). The CHIT1 gene is currently known to possess 13 exons with sizes ranging from 30 to 1055 bp (NG_012867.1, National Center for Biotechnology Information, 2012; http://www.ncbi.nlm.nih.gov/gene/ 1118).…”

Assessment of Partially Deoxygenated Deoxynojirimycin Derivatives as Glucosylceramide Synthase Inhibitors

“…Treatment of mildly affected type 1 Gaucher patients with this agent results in sufficient pharmacological lowering of glucosylceramide to levels that the residual mutant glucosylceramidase (GBA1) can deal with. 6 We have reported on the development of much more potent (for instance, 2) and also more selective with respect to other glycoprocessing enzymes (for instance, 3) N-alkylated deoxynojirimycin derivatives. 7,8 Coinciding with these discoveries, recent studies strongly point toward GCS as a therapeutic target in several diseases areas: next to lysosomal glycolipid storage disorders other than Gaucher, also type 2 diabetes, hepatosteatosis, artherosclerosis, inflammatory diseases, and polycystic kidney disease.…”

Guidance on the use of miglustat for treating patients with type 1 Gaucher disease

“…In 1994, proof of concept for this approach, commonly referred to as ''substrate reduction therapy'' (SRT) and first proposed by Radin in 1982 [10], was demonstrated using miglustat in an in vitro model of Gaucher disease [11]. Other small-molecule inhibitors of glucosylceramide synthase with greater specificity and potency have also been shown to be effective in reducing stored substrate in vitro and in animal models of lysosomal storage diseases [12], but to date miglustat is the only compound that has been evaluated in human clinical trials and shown to have some effect on visceral, biochemical, and, to a lesser extent, hematological abnormalities in patients with type 1 GD [13].…”

“…Clinical Trial 1: Study OGT918-001 and Extension Study OGT918-001X [13][14][15]17,18] Twenty-eight patients who were unable or unwilling to receive ERT participated in this open-label, noncomparative, safety-and-efficacy trial of miglustat given orally (po) at 100 mg three times daily (TID) [13]. The primary efficacy variables were percent change in volume for spleen and liver, and the actual change from baseline for hemoglobin and platelets.…”

“…The primary efficacy variables were percent change in volume for spleen and liver, and the actual change from baseline for hemoglobin and platelets. After 12 months of treatment, liver volumes (N ¼ 17) decreased by 14% and spleen volumes (N ¼ 14) decreased by 22% [13]. A nonsignificant ''upward trend'' was seen in hematologic variables (Table I) [13] Six patients discontinued from this study: one due to a serious adverse event (SAE) [peripheral neuropathy], two because of diarrhea, and three for reasons unrelated to the medication.…”