Substrate reduction therapy (SRT) is a popular small molecule currently in use or in clinical development for the treatment of LSDs. SRT aims to slow down the production of storage material rather than degrade it. CD BioSciences offers specialized SRT drug discovery solutions for LSDs.
Background of Substrate Reduction Therapy for LSDs
Advances in the genetic, biochemical and pathological mechanisms of lysosomal storage diseases (LSDs) have been made over the past decade, but the number of approved therapies remains low (~70-80). The drug development industry looks for potential LSDs treatments covering a broader and more diverse range of therapeutic modalities, from enzyme replacement, gene therapy and cell/organ transplantation, to small molecule therapies. However, most LSDs involve pathological changes in the brain and peripheral tissues, and effective treatment of central nervous system (CNS) and peripheral manifestations remains a considerable technical challenge. Substrate reduction therapy (SRT) involves the use of small molecules to inhibit the enzymes that synthesize the substrate (or one of its precursors) that accumulates in a given LSDs in order to restore the synthesis/degradation balance. SRT uses an orally available, small molecule drug that inhibits the first committed step in glycosphingolipid biosynthesis.
Fig. 1. Substrate reduction therapy for lysosomal storage disorders. (Coutinho MF, et al., 2016)
Solutions
To maximize the potential for intervention in LSDs, our scientists focus on the various steps around the defective enzyme in the metabolic pathway to find possible therapeutic targets. Based on our years of experience studying small molecules in LSDs, CD BioSciences has successfully developed substrate reduction therapy as an emerging therapeutic strategy for LSDs by reducing the amount of substrate entering the lysosome, thereby compensating for the catabolic defect. Intriguingly, rather than directly correcting the enzyme defect, our SRT solutions are designed to attenuate the bioavailability of compounds that cannot be fully metabolized by the defective enzyme.
Our small molecule drugs for SRT can be used to partially inhibit the biosynthesis of compounds that accumulate in the absence of specific lysosomal enzymes, thereby reducing the number of molecules within the lysosome that need to be catabolized, thereby helping to balance the rate of synthesis with the impaired rate of catabolism. CD BioSciences offers custom SRT drug discovery solutions for LSDs.
Development of Small Molecule Drugs for SRT
❖ Inhibits a key enzyme in glycosphingolipid GSL biosynthesis, ceramide glucosyltransferase.
❖ Interferes with the metabolic pathway in glycosaminoglycan (GAG) synthesis.
❖ Gene SRT: We have advanced gene repression technology to selectively downregulate genes involved in the biosynthesis of accumulated substrates. This is a fully molecular, drug-free approach.
Preclinical Evaluation of Small Molecule Drugs for SRT
We construct in vitro models of Gosher disease, measure them by thin-layer chromatography, and observe electron-dense lysosomal stores by electron microscopy. In addition, we have real, well-characterized animal models of LSDs (spontaneous and engineered) for testing the efficacy of experimental therapies.
Properties of SRT
- SRT is administered using small molecule inhibitors that can be administered orally.
- SRT is non-immunoreactive.
- SRT is particularly useful in toxic LSDs where accumulation of toxic metabolites leads to acute clinical failure.
- SRT is also beneficial in other LSDs in which the accumulated metabolites are complex polymers that are improperly stored in cells over time due to enzymatic defects.
- SRT uses a single compound to treat multiple disorders as well as the potential to reduce brain storage.
- SRT is used not only as a monotherapy, but especially as a complementary approach to LSDs.
We are very innovative in the development phase to achieve each client's individual goals. We are ready to explore the value of SRT to meet the requirements of novel LSDs treatment strategies. For more information, please feel free to contact us.
Reference
- Coutinho MF, Santos JI, Alves S. (2016) Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders. Int J Mol Sci. 17(7):1065.