01/Nov/2014 At its facility at MGH East in Charlestown, the Mass General Institute for NeuroDegenerative Disease (MIND) houses the world’s premier laboratories investigating neurodegenerative diseases including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). What’s coming out of those labs is not just new knowledge about the causes of these devastating diseases, but also a host of experimental new treatments—a bench-to-bedside success story that is unique to MIND in both the number of potential treatments being tested, and the speed at which new therapies are entering clinical testing.
What is the recipe for this success? Michael Schwarzschild, MD, PhD, a neurologist and director of MIND’s Molecular Neurobiology Laboratory, explains one reason is the unique organization of the institute’s research program around the problems patients and their physicians face. “MIND investigators are clinicians who are passionate about a particular disease, and bring that passion to the lab to help frame research questions,” Schwarzschild explained. That clinical orientation ensures that the results of work in animal models and other laboratory studies can move as quickly as possible to new treatments, he said.
Recent advances in Schwarzschild’s lab and others highlight the fruitfulness of MIND researchers working between labs and across disciplines, reaching out to make the connections that ultimately move experimental observations to new treatments.
Protecting against Parkinson’s disease
A prime example of cross-disciplinary success is Schwarzschild’s most recent clinical trial of an antioxidant to slow the progression of Parkinson’s disease. Oxidative damage—the accumulated wear and tear that occurs in brain and other tissues over the years—is implicated in many neurodegenerative diseases. Luckily, the body has defenses against such damage. One is urate, a chemical that belongs to a family called purines, which includes caffeine. When urate levels get too high, it can lead to gout and kidney stones, but at normal levels, urate may function as a potent antioxidant and neuroprotective agent. And based on large epidemiological studies, researchers have known for some time that the more urate people have in their blood, the less likely they are to get Parkinson’s.
After learning of the link between urate and PD, Schwarzschild wondered if urate might also slow the progression of disease in people who already had Parkinson’s. He did his own epidemiological study looking at 800 people newly diagnosed with Parkinson’s disease, who had only mild symptoms. He found that people with high urate levels in blood and brain had slower rates of worsening of the disease.
With funding from the Michael J Fox Foundation, Schwarzschild and colleagues were able to quickly move to clinical trials. Working with physicians across the United States, they tested the effects of giving Parkinson’s patients the nutritional supplement inosine, which is converted to urate in the blood. Earlier this year, Schwarzschild’s group published results of that study, showing that inosine is safe, has few side effects and can raise urate levels in the blood and brain. The trial also showed a hint of slower progression of Parkinson’s, especially in women whose urate levels were increased. That small study set the stage for a more definitive upcoming trial trail of inosine to slow progression of Parkinson’s.
At the same time, the investigators have revved up exploration of urate in animal models, to understand exactly how the protective effects occur. They have new clues on how urate works, which may lead to other ways of elevating urate, or of mimicking its effects with even more potent drugs. In addition, they are looking at the effects of urate in animal models of other neurodegenerative diseases like ALS, Huntington’s disease and Alzheimer’s disease. Inspired by the work of the Schwarzschild group in Parkinson’s, his collaborators MIND have recently discovered similar epidemiological evidence for a protective role of urate in ALS, and will soon begin a trial of inosine in that disease.
From a gene to potential treatment
Huntington’s disease is a rare but devastating neurodegenerative condition, striking at middle age, and causing an unrelenting, progressive loss of physical and mental capability. Huntington’s is passed down from parent to child: if a parent has HD, their child has a 50 percent chance of inheriting the disease. MGH researchers led efforts that uncovered the gene for HD in 2003, and before long, Steven Hersch, MD, PhD, was making use of a transgenic mouse that carried the disease gene and replicated many of the symptoms of Huntington’s. Hersch, now a professor of neurology and a MIND member, soon found with his collaborators that creatine, another nutritional supplement and neuroprotective energy modulator, could effectively prevent or reverse the development of HD in the mice.
Because there is a definitive genetic test for HD, researchers can identify young, healthy adults who are destined to develop the disease, and target preventive treatments towards those people. The problem is that 90 percent of people at risk do not get tested. MIND researcher Herminia Diana Rosas, MD, Director of the Center for Neuro-imaging of Aging and Neurodegenerative Disease said that is understandable. “The knowledge is not benign,” Rosas explained. A positive test for a fatal disease with no effective treatment can be personally devastating. On top of that, people have concerns about privacy and disclosure of their genetic status.
But the reluctance to test means that few of those at risk are available for preventive trials, which would typically require participants to have genetic testing. To address that problem, Hersch and Rosas collaborated to design a revolutionary clinical study that would ask if high-dose creatine could prevent Huntington’s in healthy people at risk for the disease, without requiring genetic testing.
“This was the first prevention trial to look at people who are not sick yet, but who may be genetically destined to get disease,” said Rosas. The design works because on average, half of the untested at-risk people have the gene, and the other half serve as a control group. “Because we did not require them to get genetic testing, this will greatly expand the availability of trials to patients, while protecting their privacy.”
The trial was also the first to use magnetic resonance imaging (MRI) to look at changes in brain structure during drug treatment, and found that creatine appeared to slow brain shrinking associated with Huntington’s. This could help speed up future trials, because the brain changes appear earlier, and progress much more quickly than clinicians can see changes in outward symptoms of the disease.
The results of the study, published in March 2014, show that creatine is safe and well tolerated, paving the way for more definitive studies, including brain scans in more patients. Hersch and Rosas are also working on blood and cerebrospinal fluid tests that could also help track the progress of the disease or the effects of treatments.
A team effort on ALS
Merit Cudkowicz, MD, MSc, is quick to point out that she is not a bench scientist, but instead a catalyst bringing together clinical and bench scientist to push forward new treatments for ALS, also known as Lou Gehrig’s disease. Cudkowicz, a professor of neurology, is also the founder of the NorthEast ALS Consortium (NEALS), which involves clinicians and neurobiologists at centers across the US in research and testing of new treatments for ALS. “We needed to get scientists and clinicians to know each other and work together, because that speeds things up,” she said.
As a result of this collaborative approach, ALS is leading the neurology field in the hunt for treatments for neurodegenerative diseases, Cudkowicz said. “We are testing really novel treatments, including multiple drug studies, gene therapy studies and two stem cell trials.”
“We don't have many therapies that are effective in people yet but we have set up the teams and processes to be able to get there quickly,” she said.
That is no small feat, given that not long ago, the cause of ALS was still a complete mystery. Then, in the mid-1990’s, while Cudkowicz was a fellow in neurology at MGH, her mentor identified a genetic cause for one form of ALS. People with ALS suffer a progressive degeneration of motor neurons that leads to paralysis and death, and soon after the discovery of the first gene, a transgenic mouse that mimicked the human disease was created. “It changed the field,” she said. “Before that we had no idea where to start with treatments. Suddenly, we had a model, and we started to think we could treat it.”
With NEALS, Cudkowicz has just finished a small, early stage trial with a novel DNA-based treatment targeting that gene, called SOD1. That trial showed the drug to be safe. Partnering with the companies Biogen and ISIS, Cudkowicz and colleagues plan to start additional tests soon. While the trial was groundbreaking, “the real pioneers were the first 23 patients to get the treatment,” Cudkowicz said. “One of our goals is to ensure that patients have access to trials,” she added. With 100 centers in US and Canada, and now a European equivalent of NEALS, the net effect is that most patients with ALS can participate in experimental treatments.
With efforts like these three, MIND researchers continue to work across disciplines and at the interface of basic research and clinical insights. They do that because they know it is the best way, and the best hope, for delivering new treatments to patients and families suffering currently untreatable neurological diseases.