Discovery of a genetic mutation followed by years of work by one Sanofi scientist and his team point the way to new optimism for patients.
Millions of people live with Parkinson’s disease, a chronic neuro-degenerative condition that causes damage to a part of the brain and significantly affects movement and speech in ways that make daily life challenging for patients.
While the exact causes are unknown, an estimated 5 – 10% of cases are linked to a genetic mutation that is also found in people who have a rare disorder known as Gaucher disease. It was the unexpected discovery of that link, first suggested in 2001 and 2004 papers, that inspired one Sanofi scientist to pursue more than a decade of work to unlock the genetic secrets of Parkinson’s disease.
Now the efforts of Pablo Sardi and his team are being put to their most stringent test yet: A Phase 2 clinical study of a potential treatment for that rare form of Parkinson’s, whose outcome also could significantly broaden our understanding of other more common forms of the disease. It’s a big step in a long scientific journey that’s far from over, and a journey that is frequently frustrating.
“Success in treatments for neurological conditions like Alzheimer’s or Parkinson’s has been quite scarce because we’re trying to target treatments toward the larger population,” said Sardi, PharmD, PhD, and R&D Director in Neuroscience for Sanofi. “But we know that all patients aren’t the same. In this case, while there’s still a lot of data missing, having one gene to target gives us a rare opportunity to succeed.”
The discovery that inspired years of research by the half-dozen members of Sardi’s core team came from the observation of patients with Gaucher disease, a rare and debilitating condition that occurs in people who inherited two defective copies of the glucocerebrosidase (GBA) gene – one from each parent. A GBA mutation reduces the levels of this enzyme and allows lipids called glycosphingolipids to build up in cells. Gaucher disease can cause organ and nervous system damage, along with reduced life expectancy.
Genzyme scientists have studied GBA mutations since the 1980s and went on to introduce the first treatment for Gaucher disease in 1991. That work continued when Genzyme was acquired by Sanofi.
In 2004, a few researchers working with Gaucher disease patients reported that, as their patients aged, some of them also developed Parkinson’s disease. Even more intriguing was that Parkinson’s disease was frequently seen in the otherwise healthy relatives of patients with Gaucher disease.
“So this work really started when the clinicians saw a possible connection,” said Tanya Fischer, MD, PhD, Global Project Head of Early Development for Parkinson’s Disease and Movement Disorders, Sanofi. “The idea was that single GBA mutations could be a genetic risk factor for Parkinson’s disease.”
Early on, there was considerable skepticism among researchers about the link, and those initial uncertainties meant “it took a lot of courage by senior management to let us go forward,” Fischer said. It took five years until another paper, in 2009, demonstrated a strong association between GBA mutations and Parkinson’s disease.
It also took determination by Sardi, who was faced with a range of challenges. First, he had to attempt to work out the actual mechanism of the disease. Then, he needed to persuade other colleagues that the molecule they were developing as a potential therapy for neuropathic Gaucher disease should be explored in his work on Parkinson’s.
“We have always been committed to investing in research in rare diseases in general, and that includes trying to improve care for Gaucher disease patients. We were lucky that when this link with Parkinson’s was made, the Gaucher team was already studying this molecule,” he said.
What made it particularly interesting was the ability of the molecule to cross the blood brain barrier. This is a difficult task, because the composition of the barrier is relatively impermeable to larger proteins and an array of other components of drug therapies.
Meanwhile, in exploring the mechanism of the disease, Sardi’s extended team noted areas of the brain that appeared to be affected by Parkinson’s disease. In preclinical studies he and his colleagues were able to see that the accumulation of glycosphingolipids in the brain resulted in memory deficits and that the introduction of GBA enzyme to the brain could reduce those deficits. These findings warranted further clinical studies to address the level of GBA activity as a viable therapeutic strategy. When his research associates showed the data for the first time, Sardi recalled, it was stunning. “I still get goosebumps when I remember it,” he said.
“Genetics has revolutionized our understanding of Parkinson’s disease," says Brian Fiske, PhD, Senior Vice President of Research Programs at The Michael J. Fox Foundation for Parkinson's Research (MJFF). Since its inception, genetics has remained a priority area of focus for the Foundation, which has funded diverse projects in GBA since 2006. Fiske adds, "Studying how genetic mutations, such as GBA, may increase the risk of developing Parkinson's in some populations can ultimately reveal insights that may have impact for all patients."
During the decade from discovery of the GBA¬¬-Parkinson’s association to the current studies, what kept Sardi motivated was both a love of science and his personal experience.
“I’m drawn to this research in part because I had an advisor who had Parkinson’s, and I watched him deteriorate so fast,” Sardi said. “Some people become doctors so they can try to save patients one at a time, like jumping into the water to save someone who is drowning. I chose research to try to keep everyone from falling into the water.”
As the team waits for the results of the studies, they know there’s no guarantee that what worked in pre-clinical studies will be successful in patient studies. But regardless of the outcome, Fischer believes the research into this subset of Parkinson’s disease will change the way clinicians think about and test Parkinson’s.
“From a medical standpoint, this is very exciting,” she said. “Programs like this don’t come around often.”
Last update: 4/2018