What’s new in Parkinson’s disease (PD) research? At the Parkinson’s Disease Foundation (PDF), this is the question we are often asked by people with Parkinson’s and their loved ones. How soon and in what ways will scientific research help my life with PD?
Recently, we sat down with James Beck, Ph.D., PDF’s Vice President of Scientific Affairs, to ask him some of the questions that you, our readers, most frequently ask us about the state of Parkinson’s disease research.
Q. How has Parkinson’s research evolved over the past ten years?
The focus of the field has shifted in new and exciting ways. When I first came to PDF, scientists were very focused on the idea of using antioxidants to treat Parkinson’s disease. In fact, there were several large clinical trials underway to test whether compounds such as creatine and Coenzyme Q10 could treat the disease by stopping a process called oxidative stress. To everyone’s disappointment, these clinical trials failed. But there remains hope for one potential treatment of this kind that works by raising blood levels of an antioxidant called urate. As we go to press, a phase III clinical trial for that potential drug is getting underway.
At about the same time as the antioxidant trials were going on, two independent lines of research changed the focus of the field. Both were led by scientists at PDF Research Centers: Jeffrey Kordower, Ph.D., at Rush University Medical Center, and David Sulzer, Ph.D., at Columbia University Medical Center. Their results both pointed to the protein alpha-synuclein as a likely culprit in the development of PD.
Alpha-synuclein is a protein that is found naturally in the brain and body. But in Parkinson’s disease, it clumps together abnormally. We have known about the protein for quite some time, but the research of Drs. Kordower and Sulzer changed our understanding of its early role in PD, and in turn, shifted the attention of many PD researchers.
Running parallel to this research, there has been an increased focus on the genetics of Parkinson’s. We now know that for many people, small genetic variations may combine with other factors to increase the risk for, but not directly cause, Parkinson’s disease. Closer to the clinic, we have seen increased focus on research to ease the disabling nonmotor symptoms of PD, such as cognitive issues and fatigue.
Another exciting development is an increased focus on something that PDF has long believed to be central to the effectiveness of PD research: the role of people living with PD. Listening to the concerns of the community has played an important role in the development of medicines to address some of the disabling daily aspects of PD, such as dystonia, fatigue and dyskinesia.
The result of these advances is that the PD pipeline is strong, solidly based upon basic research and likely to address unmet needs in the community.
Q. What is the one single thing you find most exciting about PD science right now?
The focus on alpha-synuclein. The protein was first discovered to play a role in PD by Roger Duvoisin, M.D., whose career was launched with PDF support. Twenty years later, it has become a major target in the search for game-changing PD therapies.
The research is still at an early stage, but it is exciting. Scientists are already studying several types of drugs that would target the protein in the brain in different ways. Some of these aim to change how much alpha-synuclein is made; others, how it folds; still others, to stop it from spreading in the brain. For all of these, the goal is the same: to slow or stop PD.
The result is that we have more drug targets for anti-PD therapies than we had 10 years ago, and today’s targets are better. The PD drug pipeline is strong, and that’s exciting news for future therapy development.
Q. It is still a mystery as to how Parkinson’s begins and develops. Which theories are most intriguing to you? Are we closer to solving the mystery?
These are two critical unanswered questions. The first, understanding how PD begins, is difficult to answer. We have made progress; for example, we have discovered rare individuals who have certain inherited genetic mutations that cause PD. But even in these cases, we continue to struggle to determine just how PD starts.
The second question, understanding how PD progresses, may be easier to answer. One intriguing theory is called the prion hypothesis, which suggests that alpha-synuclein, by spreading throughout the brain, may be responsible for the progression of PD. The theory states that alpha-synuclein becomes damaged in PD and folds into an abnormal shape. This damaged form wreaks havoc on brain cells, causing them to die.
Here is where it gets interesting: the misshapen alpha-synuclein escapes the brain cells it has damaged, enters new healthy cells and damages (or infects) them too. The theory says that this cycle continues, with the protein slowly spreading PD throughout the brain, leading to disease progression and worsening symptoms.
I am hopeful that we will soon discover exactly how PD progresses and how we can interfere in this progression. It is possible that understanding this process may give us enough information to find better treatments for PD without having to understand or eliminate its root causes.
Q.You said the PD drug pipeline is stronger than ever. Among the experimental treatments that are now in development, which is closest to market?
There are several potential new drugs in clinical trials that we hope will soon be up for approval by the US Food and Drug Administration (FDA). Of these, the one with the best chance of becoming available soon is called pimavanserin (NuplazidTM). If it is approved, this drug will be the first to specifically treat the hallucinations that are experienced by many people with PD (also known as PD psychosis). Hallucinations are the number one reason for which people with PD are placed into nursing homes, and better medications are sorely needed.
In addition, there are several drugs in development that are designed to ease more well-known PD symptoms (such as tremor and stiffness) and several designed to improve upon the effects of levodopa. Time (and clinical trials) will tell how well each may help in PD.
Q. Our community urgently needs better treatments and a cure. What are the main obstacles to getting there and how can we confront them?
There are two types of obstacles: those related to our limited scientific understanding of PD and those related to how research gets done. We have already discussed several in the first category. In the second, a major obstacle is the erratic nature of funding for science. In today’s environment, support for research is hard to come by even for the most worthy projects. And when it is available, it can be difficult to keep. This means that researchers spend too much time and energy looking for funding, and not enough focused on research.
This unreliability in funding has several serious consequences, which in turn, slow scientific progress. The first is that scientists leave the field of PD. Think for a moment about typical young scientists — smart and dedicated thirty-somethings. What will they do if they cannot depend on their jobs? Unfortunately, they often take their talents elsewhere. The second is that for scientists who do stay in the field, erratic funding hampers their ability to conduct long-term projects — the type that are crucial to solving a chronic disease like Parkinson’s. This is why PDF provides long-term, stable support to teams of scientists at our two Research Centers — allowing them to focus the bulk of their energy on doing research, instead of on writing grants.
A second related obstacle, which leaves us in danger of drying up the PD pipeline, is a lack of sufficient support for basic science. Basic science is the foundation upon which all discoveries are based. It studies the building blocks of PD (the brain, neurons and chemical reactions), to provide clues that help us better understand PD. Basic science is also critical to finding new therapies. We often hear that drug research is a pipeline. At the beginning of that pipeline is basic research and at the end are clinical trials, where new drugs are tested before getting approved by the FDA. We need to keep the beginning of the pipeline well-stocked with ideas. But funding often focuses on the end of the pipeline.
Without investment in basic science, we will have nothing to test in clinical trials. PDF invests most of its annual $4 million research budget on basic science to fill the gap and keep the new ideas coming.
In addition to funding, a third but equally important obstacle is finding ways to engage people with PD in research. Over the past decade, PDF has led the way in ensuring the patient community is a part of research. We have done so in part through a program known as Parkinson’s Advocates in Research, which brings together patient advocates and researchers. In a related program, known as Community Choice Research Awards, PDF funds research based on the priorities of the community. Both of these initiatives are designed to ensure that the insights of people with Parkinson’s are shared with the researchers who are developing their new treatments. It is a powerful concept. Already, PDF has invested in four conferences to study issues the community has identified as important, including fatigue, constipation, dystonia and dementia. This will help to speed research and improve treatments.
Q. How confident should people feel about the state of PD science?
Very. Over the past ten years, progress may have been difficult to see — there were only a handful of new drugs approved. But behind the scenes, scientists have made progress in understanding how PD develops and how to stop it. More importantly, we have built a strong pipeline, filled with novel compounds that tackle PD symptoms and some that may even halt the disease itself. The future is bright.