Gaucher Disease: A Story of Science and Humanity
By Wayne D. Rosenfield, Ph.D.
October is Gaucher Disease Awareness Month, and the first day of October each year is International Gaucher Day. Until now, you most likely never heard of Gaucher Disease. Most physicians will recall some brief mention of it in medical school, perhaps as part of a list of other rare disorders. A rare disease was defined by the Orphan Drug Act of 1983 as a condition that affects fewer than 200,000 people. Gaucher Disease, affecting perhaps as many as 60,000 people globally, is the most common of a class of conditions called lysosomal storage disorders.
And here is where Gaucher Disease comes out of the textbooks to become a real-life adventure story. Roscoe Brady, MD was early in his career when he first encountered people with the unusual constellation of Gaucher disease symptoms: Bleeding, anemia, fractures, swollen liver and spleen, degenerated joints, and episodes of severe, unremitting pain. There had already been about a century of research, beginning with a doctoral dissertation at the University of Paris by Philippe Gaucher. Dr. Gaucher had puzzled over a patient who had some signs of leukemia, but who had died from something else. Dr. Brady had the benefit of later research showing that the symptoms of people with Gaucher Disease were caused by an excess of a fatty substance in their lysosomes. These lysosomes are tiny structures, inside cells. And the lysosomal storage, and then the person’s symptoms, were because of a very minor deficiency of an enzyme.
The solution seemed simple. Inject the patient with a supply of what was missing and the problem should be solved. “Voila!” as Dr. Gaucher might have said. Dr. Brady’s research team at the National Institutes of Health worked to extract the necessary enzyme from donated tissue. Painstakingly, they accumulated enough enzyme to attempt to treat a living, suffering patient.
The volunteer who had been diagnosed with Gaucher Disease received the enzyme by intravenous injection. Dr. Brady and the clinical research team anxiously checked the patient’s blood chemistry values over the coming days. There was no change in the patient’s condition. The treatment did not work.
Dr. Brady and his researchers pondered what could possibly be going wrong. They knew that they had the right chemical, an enzyme. They knew that this patient was deficient in this enzyme, which led to the symptoms and complications of the disease.
The enzyme needed to travel through the patient’s blood, through the outer walls of the body’s cells, and into the lysosomes deep inside individual cells. They knew that the enzyme’s chemical structure was that of a protein. And they realized that the body is very good at digesting proteins, especially foreign ones.
Perhaps the researchers were discouraged. But the history of science is full of accepted null hypotheses. Even a negative result adds to the body of knowledge. This enzyme replacement should have worked. What were they missing?
Scientists sometimes refer to benchwork, the tedious basic research that reveals essential truths, contributing to the body of knowledge. Truth discovered empirically adds to the body of human understanding. And we never know when we will need knowledge off the shelf. Dr. Brady learned that the membranes of lysosomes, the walls of tiny structures deep inside of other structures, have mannose ligands, tiny molecular receptors just waiting for a certain type of sugar.
“What would happen,” they wondered, “if our precious enzyme had a mannose molecule stuck onto the end of it? Would it survive the journey through the bloodstream long enough to find the lysosomes? And if it did, would the lysosome, itself a digester sort of thing, accept it inside? And once inside, would the enzyme still have enough oomph to gobble up the accumulated substance that causes the disease symptoms? And can all of this happen before the body’s own defenses against foreign invaders rip the enzyme to shreds?”
It seemed like slim odds. But success is only possible if we try. And a young boy, not even a teenager, was sick and would likely die. His mother was a physician who had followed Dr. Brady’s work for years. Her precious son would be the first to get the mannose-terminated enzyme.
I once heard this mother describe the scene of the first infusion. “It was very dramatic,” she said. The research team needed to be ready for any possible emergency. Would the boy have a life-threatening allergic reaction? Would his body respond in unexpected ways?
The enzyme dripped slowly into the boy’s intravenous line, and he remained just as happy and aware as before. In the coming days, laboratory results showed significant improvement in multiple biomarkers. Dr. Brady had done it!
The drug still needed much more testing, especially with regard to safety and effectiveness in more people, to win approval from the FDA. The first version of this enzyme replacement therapy was available for sale to the public in 1991.
Two years later, I was present at a meeting of the National Gaucher Foundation, with dozens of people who had been sick with multiple symptoms that affected their productivity, their longevity, and their ability to live normal lives. Dr. Brady took his place at the podium. There was only limited applause, because many of those in attendance were still pulling themselves up on their crutches to give him a standing ovation.
Then there was applause.
Gaucher Disease became the first lysosomal storage disorder to be treated with mannose-terminated enzyme. There are several dozen lysosomal storage disorders, some with even more devastating complications than Gaucher Disease. About five of them are now commercially treated.
But this month is about Gaucher Disease, a tenacious scientist, a brave mother and her trusting son, and the value of basic scientific research to find the Gaucher disease treatment.
Dr. Wayne Rosenfield worked for many years in Connecticut to develop and implement inpatient treatment programs for persons with chronic and debilitating mental disorders. His interest in addressing the most intense problems led him to disaster mental health deployments with the Red Cross following the 2001 terrorist attacks, and then to crisis work in hospital emergency departments. He was again with the Red Cross in Newtown the day after the shootings at Sandy Hook Elementary School. Engaged with Connecticut’s response to Sandy Hook he was part of a statewide initiative to treat trauma in children. Having relocated to Florida, he is part of a research team examining a novel treatment for combat PTSD, and he performs psychological assessments for a group practice. He is a frequent speaker in the US and internationally on the subject of rare diseases. He is a professor in the Argosy University School Psychology program in Sarasota. His highly rated book, Great Necessities, is available on Amazon.com.