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Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation

Journal of Clinical Investigation, ISSN: 0021-9738, Vol: 105, Issue: 11, Page: 1563-1571
2000
  • 151
    Citations
  • 0
    Usage
  • 55
    Captures
  • 2
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    151
    • Citation Indexes
      149
    • Clinical Citations
      1
      • PubMed Guidelines
        1
    • Patent Family Citations
      1
      • Patent Families
        1
  • Captures
    55
  • Mentions
    2
    • References
      2
      • Wikipedia
        2

Article Description

We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in α- galactosidase A (α-gal A) knockout mice, a model of Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo-1-ethylendioxyphenyt-2- palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4) showed a concentration- dependent decrement in glucosylceramide levels in kidney, liver, and spleen. A single intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide metabolism. A concentration-dependent decrement in renal and hepatic globotriaosylceramide levels was observed in α-Gal A males treated for 4 weeks with D-t-EtDO-P4. When 8-week-old α-Gal A males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an α-galactosidase A-independent salvage pathway for globotriaosylceramide degradation. Complications observed with another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, including weight loss and acellularity of lymphatic organs, were not observed with D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to substrate deprivation therapy.

Bibliographic Details

Akira Abe; Susan Gregory; Lihsueh Lee; James A. Shayman; Paul D. Killen; Roscoe O. Brady; Ashok Kulkarni

American Society for Clinical Investigation

Medicine

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