A recent review of substrate reduction therapy for Gaucher disease, by the National Health Institute Doutor Ricardo Jorge, in Portugal, explored how well the strategy performs and identifies areas of treatment improvement for Gaucher and other lysosomal storage disorders.
Gaucher disease, caused by the lack of an enzyme called glucocerebrosidase, is typically managed with enzyme replacement therapy – which is considered far from optimal. Because lack of the enzyme causes accumulation of fatty material (glucocerebroside) throughout the body and bloodstream, substrate reduction therapy – which reduces glucocerebroside (a lipid) – could be a better option.
The review, “Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders,” and published in the International Journal of Molecular Sciences, suggests that limiting the production of the lipid aggregating in Gaucher is a promising method to reduce symptoms — and that more therapies need to be developed.
Enzyme replacement therapy, the simpler way to approach diseases like Gaucher when a dysfunctional enzyme leads to the buildup of fats, is limited because it does not reach target organs such as bone, lungs, and brain. The therapy can also elicit immune responses making them even less effective; and they need to be administered through intravenous infusions.
The idea that disease symptoms can be prevented by lowering the production of the fat that chokes the system up is a more attractive option.
Substrate reduction therapy can be accomplished through oral drugs, and can theoretically be designed to reach the brain, an organ rarely affected in Gaucher but when involved causes more severe symptoms.
In 2003, the U.S. Food and Drug Administration (FDA) approved Zavesca (miglustat) for mild to moderate Gaucher disease type 1, which had been approved by the European Medicines Agency a year earlier. Clinical trials failed to show improvement in the more severe Gaucher type 3, which affects the brain.
The drug was developed as a blocker of CGT (ceramide glucosyltransferase), an enzyme that participates in the production of the lipid accumulating in Gaucher. Later reports discovered that the drug also blocked another enzyme, adding to its efficacy. Although the drug has improved treatment, and proved that reducing the production of the type of lipids that aggregate in Gaucher is a viable treatment strategy, there are downsides to the treatment.
High-dose enzyme replacement treatments often reach better results but the drug causes side-effects such as diarrhea. The risk of triggering developmental effects in fetuses makes it also unsuitable for women of childbearing ages.
More recently, Cerdelga (eliglustat tartrate) was approved both in Europe and in the U.S. The drug only targeted Gaucher disease type 1, showed an effectiveness that compared to enzyme replacement treatments, and was superior to Zavesca.
But Cerdelga is also unable to reach the brain. The need for drugs with this feature remains. Other drugs are under development. Genzyme, the developer of Cerdelga, has several compounds in development.
Recent studies have also pointed to the improved efficacy of treatments combining enzyme replacement with substrate inhibitors, or in the case of other storage disorders, substrate inhibitors with anti-inflammatory drugs. The combinations are showing positive results.