Substrate reduction therapy is an investigational way of possibly treating lysosomal storage disorders that include Pompe disease, a rare genetic condition in which damaging levels of a complex sugar molecule called glycogen accumulates inside cells due to a deficiency in the acid alpha-glucosidase enzyme.

How substrate reduction therapy works

Enzymes are specialized proteins that can modify certain molecules. The molecule that an enzyme modifies is called that enzyme’s substrate. Each enzyme has its specific substrate. There are several enzymes and substrates in a metabolic pathway, a chain of biochemical reactions that degrade and generate molecules.

Pompe disease is caused by mutations in the GAA gene, which contains the information necessary to make the enzyme acid alpha-glucosidase. This enzyme is responsible for breaking glycogen into glucose in the lysosomes, cellular compartments filled with digestive enzymes that degrade large molecules.

In Pompe patients, glycogen builds inside cells due to a lack of functional acid alpha-glucosidase, leading to severe muscle weakness and other disease symptoms.

Substrate reduction therapy is a small-molecule treatment for lysosomal storage disorders that works to partly inhibit, or block, the biosynthesis of big molecules like glycogen to correct the imbalance created by the gap between their formation and their breakdown into smaller molecules like glucose. In other words, it helps to prevent glycogen storage not by correcting the enzymatic defect but by lowering the levels by which this substrate is synthesized.

Substrate reduction therapy research

Substrate reduction therapy has shown promise in tests in other lysosomal storage disorders, such as Fabry disease. There are no clinically available substrate reduction therapy options for Pompe disease yet, but researchers are working on experimental cell and mouse models that might lead to a treatment for Pompe patients.

Two enzymes make glycogen in the cells: glycogenin (GYG), and glycogen synthase (GYS). One study tested whether knocking out the GYG or GYS genes in mouse muscle cells grown in the laboratory that also lack the GAA gene could reverse glycogen accumulation. Indeed, while cells that lack the GAA gene had elevated levels of glycogen, cells that were deficient in GYS or GYG genes in addition to the GAA gene had significantly lower levels of glycogen.

In another study, the same research group used live mice that were genetically engineered to lack the GAA gene (GAA deficient mice) in order to model Pompe disease. These mice show the main symptoms of Pompe, such as glycogen accumulation in the heart and skeletal muscles, as well as muscle weakness. The work showed that when these mice were further engineered to give birth to pups without the GYS gene, the newborn mice had no glycogen accumulation and normal-size hearts.

Recently, a research group described the first genetic substrate reduction therapy for Pompe disease by decreasing GYS gene activity in Pompe mice via an injection of a gene modifying molecule complex, called a morpholino oligonucleotide.

In this study, mice that received the injection had significantly lower levels of glycogen in their muscles, including their heart muscles. However, this method was found to be toxic to the kidneys. Researchers suggest that if a less toxic version of this molecule complex could be developed, it might be tested in clinical trials as a possible treatment for Pompe disease.


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