Researchers identified a bew small molecule that, in a mouse model, effectively eased manifestations of Gaucher disease, and suggested that this molecule, called Genz-682452, may offer is a new therapeutic approach for patients with type 3 disease.
The study, “CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease,” was published in the journal Nature Molecular Therapy.
Gaucher disease is a genetic condition caused by the lack of an enzyme (glucocerebrosidase, or GBA), which is responsible for the breakdown of fatty substances in the body. In the absence of the enzyme, these fatty substances accumulate in different organs, including the brain, and can cause neuronopathy (neuron degeneration).
The researchers, from Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, College of Medicine, working in collaboration with scientists from the biotechnology company Sanofi Genzyme, evaluated the efficacy of Genz-682452 in treating brain disease.
First, the team induced neuronopathic Gaucher disease in mice with a substance that blocks the activity of the enzyme that is defective in patients. The scientists next treated the mice with Genz-682452, and saw that the levels of harmful substances, which accumulate as a result of the condition, were reduced by more than 70% in the brain and by more than 20% in the liver.
Pathological changes that occur in the glial cells of the central nervous system in response to damage (gliosis), and the severity of the lack of voluntary muscle movement and coordination (ataxia), were also less extensive after treatment. Importantly, the lifespan of treated mice also increased by around 30%.
Genz-682452 works by inhibiting an enzyme, which is responsible for the production of the substrates of the enzyme — GBA — that is defective in Gaucher patients. Genz-682452 is also able to cross the blood-brain barrier and is orally available.
Other approaches to tackle Gaucher disease include enzyme replacement therapy, where the deficient enzyme is replaced by artificial enzymes. But this therapy can cause an allergic reaction and hypersensitivity in patients. Enzyme replacement therapy is also not efficient in managing the brain involvement seen in type 2 and 3 Gaucher disease.