Substrate Reduction Therapy

Research team:

  • Gustavo H. B. Maegawa, Joe T. R. Clarke, Metabolics, SICKKIDS, ON, Canada;
  • Brenda Banwell - Neurology, SICKKIDS, ON, Canada;
  • Cynthia Hawkins and Cameron Ackerley - Pathology and Laboratory Medicine, SICKKIDS, ON, Canada;
  • Jason Hayes - Surgery, SICKKIDS, ON, Canada;
  • Cynthia Tifft - Children's National Medical Center, George Washington University School of Medicine, USA;
  • Maggie Tlopak and Geoffrey Sorge - Department of Psychology, Faculty of Health, York University, York, ON, Canada;
  • Susan Blaser - Diagnostic Imaging, SICKKIDS, ON, Canada;
  • Paul van Giersbergen - Dept. of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland



Substrate reduction therapy in juvenile GM2 gangliosidosis

Gustavo H.B. Maegawa, Brenda L. Banwell, Susan Blaser, Geoffrey Sorge, Maggie Toplak, Cameron Ackerley, Cynthia Hawkins, Jason Hayes and Joe T.R. Clarke

Molecular Genetics and Metabolism, Vol. 98, Issues 1-2, Pgs 215-224, Oct. 2009


Research Background

N-butyryldeoxynojirimycin (NB-DNJ), a galactose analog, was shown to be competitive inhibitor of (glucosidases I and II, glycohydrolases in the ER that are II are required for the capside biosynthesis of retrovirus (Platt et al., 1992). The potential of the drug for the treatment of HIV-AIDS prompted Monsanto to sponsor extensive preclinical and clinical trials, which failed because of the high dose needed to achieve alpha-glucosidase inhibition, caused severe osmotic diarrhea (Fischl et al., 1994), explained by inhibition of intestinal dissacharidases.


NB-DNJ was also found to be a potent competitive inhibitor of ceramide-specific glucosyltransferase (GtcT-1, glucosylceramide synthase; UDP-glucose-N-acylsphingosine D-glucosyltransferase; E.C., which is responsible for the catalyzing of the first step in the glycosphingolipid (GSL) biosynthesis (Platt et al., 1994). The minimal N-alkyl length of three-carbon chain is critical for the inhibitory effect on over GlcT-1 (Platt et al., 1994). The first clinical evidence that NB-DNJ could function as a SRT came from evaluation of substrate deprivation in a cell model of Gaucher disease (GD). Treatment with NB-DNJ produced substantial reduction of the accumulated glucoceramide in these cells was achieved using different concentrations of NB-DNJ (Platt et al., 1994). More recently, NB-DNJ was shown to function as a SRT in a Tay-Sachs mouse model (Platt et al., 1997). An almost 50% reduction of GM2 storage in the brain was observed in all animals treated with NB-DNJ. This was a significant finding showing that NB-DNJ is able to cross the blood-brain barrier (BBB) to an extent sufficient to decrease GM2 storage (Platt et al., 1997). Sandhoff mouse models were also treated with NB-DNJ, showed increased life expectancy (by ~40%) (Jeyakumar et al., 1999).


The potential application of NB-DNJ for the treatment of GD was explored in one year open-label phase I/II clinical trial was performed in type 1 Gaucher disease (GD-1) patients from UK, Netherlands, Czechoslovakia and Israel (Cox et al., 2000). A total of 28 patients were enrolled in the study, all of them naïve to enzyme replacement therapy. The major DRAE in this study was diarrhea (79%). In most patients the diarrhea resolved spontaneously within several weeks and was not a limitating symptom (Cox et al., 2000). Weight loss (up to 6% of baseline weight) was also a significant DRAE, and shown to be as frequent as diarrhea (Heitner et al., 2002, Zimran and Elstein, 2003). After 12 months on NB-DNJ, GD-1 patients showed 19% and 12% reduction of spleen and liver sizes respectively (Cox et al., 2000). Improvement of hematological parameters such as hemoglobin and platelet count was also observed in this and further studies (Pastores et al., 2007, Weinreb et al., 2005). Niemann–Pick disease type C (NPC), a genetic lipid storage disorder most commonly caused by mutations in NPC1 (encodes a membrane protein involved in endosomal–lysosomal transport of lipids), was another LSD in which SRT was tested. Patterson et al. reported recently a study of patients aged 12 years or older which were randomly assigned in a 2:1 ratio to either miglustat 200 mg taken orally three time daily for 12 months, or to standard symptomatic care (no drug given) as a control group. Improvement in horizontal saccadic eye movement velocity of similar size, swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were seen in treated patients older than 12 years (Patterson et al., 2007).


Five patients received miglustat and were followed for 24-months by our team at The Hospital for Sick Children, Toronto, Canada. Data from pharmacokinetics, safety, tolerability and efficacy (derived from specific neurological clinical outcomes, psychological tests, electrophysiological and brain imaging studies) were obtained. We collaborated with Dr. Cynthia Tifft MD, PhD from Children’s National Medical Center, Washington, DC, US, who also recently completed phase I/II clinical on SRT in infantile GM2 patients.