In an important breakthrough, researchers at Yale School of Medicine have found that new disease pathways involving more than one cell type leads to Type 1 Gaucher disease, a rare genetic disorder resulting in liver/spleen enlargement, low blood counts, osteoporosis, bone pain, and increased risk of cancer and Parkinson's disease.
The new findings could lead to less expensive and more effective ways to treat the disorder, which affects about 1 in 50,000 people in the general population.
“In order to tailor treatment to individuals and to treat all aspects of the disease and not only part of the disease as we do currently, we need an improved understanding of the disease mechanisms,” says Yale Medical Group’s Pramod Mistry, MD, senior author of the study, who spoke about the discovery in an article in the Hartford Courant.
People of Eastern and Central European (Ashkenazi) Jewish heritage are at highest risk for the disease, with 1 in 750 affected. Treatment for Type 1 Gaucher disease involves expensive recombinant enzyme infusions every two weeks for life, which on average costs $200,000 per year. Gaucher disease symptoms are unpredictable, even among affected siblings.
Model replicates the disease
For almost 20 years, investigators around the world have tried and failed to develop mouse models of Type 1 Gaucher disease that replicate the human disease faithfully. Mistry and his team were able to develop a mouse model that replicates all of the features of the human disease.
It was previously thought that the disease affects only one cell type in the body called macrophages. “In our study we show that all cell types are involved and lipids that accumulate trigger abnormal signaling resulting in the malfunction of many cell types,” says Mistry. “This helps explain aspects of the disease, such as osteoporosis, cancer risk, and risk of Parkinson’s disease, all of which did not respond to macrophage-directed enzyme therapy. With this knowledge, we can look forward to developing treatments that are directed not only to macrophages, but to all cell types involved in the disease process.”
The study was published in the Proceedings of the National Academy of Sciences. It gained attention from Gaucher researchers earlier this year when it was presented at a conference in Europe. Neal Weinreb, regional coordinator of the International Collaborative Gaucher Group, says, “Many people said it was probably the most important paper that was presented this year."
Trial starts on better medication
Mistry and his team have just started enrolling patients in an international trial of a small molecule substrate inhibitor—in the form of a pill, which was developed by Genzyme Corporation. “Because it is a pill and will affect all cell types, we expect it to reverse all, not just part, of the disease. Also, it should be less expensive than enzyme treatment,” Mistry says. They estimate it would be four years or more before the medication is available.
Relatively little is known about Gaucher disease because it’s so rare, Mistry says. "We did a study a few years back when we found that patients are often misdiagnosed for many years before the correct diagnosis of Gaucher disease was made," he told the Courant in an e-mail.