When Pramod Mistry, MD, a Yale Medicine expert in inherited liver diseases, cared for his first patient with Gaucher disease 35 years ago, he didn’t anticipate that his work with this rare genetic disorder might illuminate the understanding of more common conditions such as multiple myeloma and Parkinson’s disease.
Dr. Mistry, director of the National Gaucher Disease Treatment Center at Yale, has focused his career on Gaucher, which affects one in 40,000 people worldwide. The disease is characterized by fat-filled cells that accumulate in parts of the body including the liver, spleen, and bone marrow; in some forms of the disorder, the brain, lungs, and lymph nodes are also affected. This buildup causes inflammation, enlarged organs, bone pain, and other disabling symptoms, while also raising the risk for fracture.
In 2001, a patient of Dr. Mistry’s with Gaucher disease also developed multiple myeloma, a type of blood cancer, which affects plasma cells in the bone marrow. “Why did I get multiple myeloma?” the patient asked Dr. Mistry. It was a good question. At that time, there were a few isolated case reports of people with Gaucher being diagnosed with multiple myeloma, but the connection was not understood.
Dr. Mistry’s patient, a physician, followed up by also asking, “What is the mechanism here, and what can be done about it?”
“I took that question to heart,” Dr. Mistry says. “Everything starts and ends with patients. First, we conducted a Yale-focused study in one of the largest groups of patients in the world and then expanded to an international cohort. Our research taught us that the fat-filled cells called macrophages talk to immune cells called B-lymphocytes, which produce excessive amounts of antibodies, and unchecked, it leads to multiple myeloma.”
The Yale study, published in 2009, was the first comprehensive analysis demonstrating that Gaucher disease increased the risk of myeloma by 25-fold compared to the general population, Dr. Mistry says. The next step was to take this information to the laboratory and develop intricate mouse models of Gaucher disease. “We learned that the accumulation of this fatty material in macrophages, the scavenger cells of the body, triggers an inflammation of the immune system to be activated in such a way that B-Lymphocyte, starts to make antibodies to the lipid,” he says.
Based on the lab study, that activation of the immune system is believed to eventually cause a sequence of events, he explains, that leads to the development of multiple myeloma. With a hypothesis to explain this process, Dr. Mistry led an international clinical trial testing a pill that slows the Gaucher disease process, replacing the traditional biweekly infusion treatments. This drug, eliglustat (Cerdelga®), was FDA-approved in 2014, marking a significant advance in Gaucher disease therapy. Further studies indicated that this pill not only treated Gaucher symptoms but also reduced the precancerous conditions associated with multiple myeloma. Dr. Mistry believes such treatment strategies could prevent multiple myeloma in future generations of Gaucher patients.
“When it comes to discoveries and research questions, every single major question that we've pursued in the laboratory has started with a patient asking the question,” Dr. Mistry says. “We then study it in a larger number of patients and then take it into the lab to apply the most cutting-edge technology to dissect the problem. Among the most important skills I try to teach my medical students is that they must develop the art of listening to their patients, because they define very fundamental questions about their disease.”
In the Q&A interview below, Dr. Mistry describes how research focusing on rare diseases can provide valuable insights into more common diseases.