What is Substrate Reduction?
Substrate reduction therapy uses 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 reduction therapy, the amount of substrate is decreased to match the amount of residual enzyme to prevent accumulation.
What is the Current Status of Substrate Reduction Research?
Several substrate reduction therapies 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.
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.
What are the Challenges of Substrate Reduction?
The primary challenge of substrate reduction 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.
Download the Subcommittee on Experimental Therapies paper on substrate reduction therapy here.