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,
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
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
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.
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
program in Sarasota. His highly rated book, Great Necessities, is
available on Amazon.com.