The treatment of Gaucher disease is poised to enter a new era as a result of advances in the understanding of the cellular pathways at work in the disorder.
Pramod Kumar Mistry, MBBS, PhD
The treatment of Gaucher disease is poised to enter a new era as a result of advances in the understanding of the cellular pathways at work in the disorder, according to Pramod Kumar Mistry, MBBS, PhD, whose research is helping to chart the future.
Mistry said researchers have been exploring the reasons that patients with Gaucher disease face an increased risk of multiple myeloma and other cancers, osteoporosis, and Parkinson disease. Neurodegenerative disorders are particularly pronounced in patients with type II and type III Gaucher disease.
He said enzyme replacement therapy (ERT ), introduced approximately 20 years ago, has made a dramatic difference for patients once consigned to disabling diseases and premature death, but that they still face a high-risk burden.
“The new generation of patients are doing extremely well, but they do carry ongoing risks. Those observations have prompted us to go back to the bench to do investigations into mechanisms of Gaucher disease,” Mistry said in an interview during ICHG/ASHG 2011. “We want to understand how these pathways intersect.”
Mistry is chief of Pediatric Gastroenterology & Hepatology, medical director of the Pediatric Liver Transplant Program, and a professor of Pediatrics and Internal Medicine at Yale University School of Medicine, New Haven, Conneticut. He also is the director of the National Gaucher Disease Treatment Center.
The center is playing a major role in the development of eliglustat tartrate, a novel oral therapy for type I Gaucher disease that is aimed at reducing levels of lipids before they can build to harmful elevations.
Last year, Mistry’s team announced the development of a new mouse model after nearly 2 decades of work. The glucocerebrosidase gene, GBA1, was deleted from the mouse, giving researchers a powerful tool to explore the cellular pathways of the disease (Proc Natl Acad Sci USA. 2010;107(45):19473-19478.)
Mutations in the GBA1 gene cause enzyme deficiencies that result in a lipid buildup in the liver, spleen, bone marrow, and nervous system.
“We were among the first groups in the world to develop a mouse model that faithfully replicates human disease, and the advantage of having a model like that is that we can really begin to define the molecular steps from the buildup of the lipids to the clinical manifestations,” said Mistry.
He said researchers no longer believe that Gaucher disease affects only the macrophage cell type (white blood cells within tissue). Instead, he said, it affects all cells in the body.
“Gaucher disease is not just a passive buildup of this fatty substance in cells. It’s not as if the cells are constipated with this fatty material,” said Mistry. “Once the fatty material begins to accumulate, it alters—dramatically—the entire genetic program of the cell.”
Mistry is particularly optimistic about the prospects for eliglustat to improve treatment. He said the small molecule nature of the drug would make it easier to produce than the biologic, injectable ERT , and that it would be more accessible for patients, particularly those in lessdeveloped countries.
Eliglustat also employs a mechanism of action that differs from ERT , he explained. “Enzyme replacement therapy is targeted just to the macrophage, and it goes to the macrophage and breaks down the lipid that has accumulated,” he said. “Eliglustat works by reducing the level of this lipid that builds up in macrophages, but it also reduces the level of lipid that builds up in other cell types.”
Mistry believes eliglustat eventually may prove to be therapeutic not only for Gaucher disease, but also for other LSD s such as Fabry disease, and perhaps even in certain cancers.
“What is really exciting about this particular molecule is that it is already being engineered in a form that may be able to cross the blood—brain barrier, and the biggest burden of lysosomal disease are the diseases that affect the brain and cause neurodegenerative disease,” he said.
“I think that the next era is going to see us not only being able to treat all of the disease in patients suffering from Gaucher disease, but we also will be able to use some of these molecules in a subset of patients with cancers,” said Mistry.