Substrate inhibitors are small molecules that pass the blood brain barrier into the
central nervous system and decrease the amount of substrate or waste product that accumulates. Think of a clogged sink with the faucet running and turning down the faucet. The water will still fill up the sink but it will take longer.
A visual representation:
a) In most individuals the substrate (water) can be degraded efficiently by adequate
enzyme volume (hole in sink).
b) In affected individuals the amount of enzyme is insufficient to efficiently degrade the substrate and it accumulates.
c) In affected individuals treated with substrate synthesis inhibitors the amount of substrate is decreased to match the amount of residual enzyme to prevent accumulation.
Several substrate inhibitors have delayed symptoms and prolonged survival in Tay-Sachs and Sandhoff mouse models but this success has not always successfully translated into the same results with humans.
Zavesca® (miglustat)
Clinical trials in babies, children and adults with Tay-Sachs and Sandhoff of the substrate inhibitor Zavesca® (miglustat) did not show therapeutic benefit. Zavesca is FDA approved for Gaucher which provides families affected by other lysosomal diseases the option of using the drug for off-label use. The FDA did not approve Zavesca® for Niemann-Pick Type C (NPC) but this use was approved in Europe and Canada.
Zavesca may have a small therapeutic effect on children affected by Juvenile GM-1. Contact our director of family services, Kim Kubilus at
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or 800.906.8723 to learn more.
The primary challenge of substrate inhibition is keeping up with the rapid accumulation of waste production. Zavesca can have significant gastrointestinal side effects such as diarrhea which was extremely debilitating to many participants in the Late Onset Tay-Sachs clinical trial.
Learn more:
http://www.parseghian.org/aboutnpc_drugtrials.html
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000259/
http://www.zavesca.com
