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Rare-disease research by Yale authors provides broad insights

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Posted February 18, 2015

Research into rare conditions, such as Gaucher disease (GD), can be challenging and often under-recognized. Two new studies by Yale scientists may not only be game-changers for individuals with GD but also offer insights into the study of other diseases, from cancer and Parkinson’s to obesity.

Yale's Dr. Pramod K. Mistry and an image from his study showing an MRI of a Gaucher disease patient with massive liver and spleen enlargement.

Yale’s Dr. Pramod K. Mistry and an image from his study showing an MRI of a Gaucher disease patient with massive liver and spleen enlargement.

Gaucher disease type 1 is a chronic disorder that causes disability, reduced life expectancy, and life-threatening complications in patients. Until recently, the main treatment option consisted of enzyme replacement therapy, provided intravenously on a biweekly basis.

To determine the utility of a novel oral therapy, eliglustat, first author Dr. Pramod K. Mistry, professor of medicine, pediatrics and cellular & molecular physiology at Yale School of Medicine, collaborated with a multinational team of researchers to conduct a study known as ENGAGE. It was the first placebo-controlled and largest randomized trial in patients with this rare genetic disease. The study was published online Feb. 17 in JAMA.

During the nine-month research period, study participants received either eliglustat or a placebo. Compared to those taking the placebo, participants taking the oral therapy showed marked improvements in GD complications. “Patients who received eliglustat had reduction in the enlargement of the spleen and liver, and improvement of platelet count, hemoglobin, inflammatory markers, and measures of bone involvement,” said Mistry.

While more research is needed, the study result strongly supported the use of eliglustat for GD type 1. “It gives patients the option of having a safe, effective, oral treatment, in contrast to intravenous infusions every two weeks for the rest of their lives,” Mistry explained.

A related study, led by Dr. Madhav V. Dhodapkar, professor of immunobiology and chief of hematology at Yale School of Medicine, looked at glycosphingolipids that are altered in individuals with GD. His study, published last month in the journal Blood, uncovered a new kind of immune cell, type II Natural Killer T (NKT) cell, that recognizes those lipids. One function of this novel cell type is to help B cells, immune system cells that make antibodies.

The finding explained a previous Yale study that showed a nearly 30-fold increased risk of multiple myeloma in patients with Gaucher disease compared to the general population.

“These patients are living longer, and the most common cause of mortality is the development of cancers, specifically B-cell tumors,” said Dhodapkar, who is also a member of the Yale Cancer Center. His research provided a new pathway to target for cancer prevention in these patients.

The rare-disease research may also provide clues for treating other conditions. A few years ago, Yale researchers demonstrated that people with GD had a 26-fold higher risk of developing Parkinson’s disease. The discovery of this genetic link was a surprise to scientists who study both diseases and promised to be a boon for future investigations.

“One implication is that the drugs developed to treat Gaucher disease may be relevant to patients who have Parkinson’s disease but are only carriers of Gaucher disease mutations,” said Mistry.

Dhodapkar’s research also identified a pathway for regulating the inflammation associated with the disordered lipids found in GD and other conditions. “Many of the lipids that are altered in Gaucher are also altered in other metabolic disorders, such as obesity,” said Dhodapkar. The drug Mistry studied, eliglustat, targets the same pathway.

Source: Yale University

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