In an editorial this summer published in Personalized Medicine, authors from The Michael J. Fox Foundation for Parkinson’s Research and J. William Langston, M.D., chief scientific officer and founder of The Parkinson’s Institute, outlined a strategy to advance precision medicine in Parkinson’s disease (PD). Lead author Todd Sherer, Ph.D., CEO of The Michael J. Fox Foundation and his co-authors believe that by pivoting from traditional definitions of disease to profile pathology by genetic and molecular changes, neurodegeneration researchers can design and test more targeted therapies with higher likelihood of success.
But challenges do remain, as precision medicine approaches are still immature in most areas of care, with PD being no exception to that. “Truly transforming PD treatment into a precision approach will require tackling key research and regulatory challenges, and the coordinated effort of the entire PD community,” the authors wrote in the editorial. “With our growing understanding of the varied paths to Parkinson’s disease, we see potential routes to personalized medicine for our field,” added Sherer. “Increased attention and collaboration in this area will mean significant advancement in the identification and testing of new treatments to prevent, slow or stop disease.”
Todd Sherer, Ph.D.
Sherer, a key architect of the foundation's strategy to define high-priority research areas for Parkinson's disease, spoke further to Healthcare Informatics about the potential of precision medicine to be effective for PD, where the challenges lie, and what the impact could eventually be. Below are excerpts of that discussion.
What should we know about the latest in Parkinson’s disease research?
There is a lot of excitement right now in Parkinson’s disease research and the conversion of that research into potentially new treatments for PD. Right now, the disease is a progressive neurological disease, and while there are some treatments for the motor symptoms, there has been nothing that targets the underlying disease process in a way that a treatment that can slow the disease. That’s what’s been missing. The challenge we have had is a lack understanding of what might be the causal factors. What molecular processes and genetic factors might be leading to the disease? To develop a drug to slow this disease, you might want to target what’s actually causing cells in the brain to die.
The exciting new advance in the last five years or so is an increase, understanding, and identification of what these causal factors for the disease could be, particularly coming out of some important genetic discoveries or molecular discoveries that can lead to PD. Some of that understanding has been converted to therapies that are being tested in clinical trials. So for the first time, we have a robust pipeline of treatments that could potentially slow the disease.
There are plenty of strong examples of precision medicine in oncology. How can this approach be applied similarly to PD?
Historically, we have known there is a great variability in the symptoms of people who have PD and also a great variability in the people who have the disease, in terms of age, cause of disease, family history, how quickly it might progress, and how they respond to medicine. There has always been a great clinical variability. Now, we have the first indications of being able to better segment and understand this patient population based on the biology and the ability of genetic factors to contribute to the disease. This is leading to a re-definition of how we’re thinking about PD where we have the potential to subset the disease by the underlying biology, which is similar to the oncology example, which is now identified and characterized by certain molecular changes, [allowing] you to develop treatments to target those molecular changes.
We are not there yet for PD in terms of having the targeted therapies, but we are gaining information to better understand the segmentation of the population and how the underlying biology could be continuing to the various expressions of the disease and ultimately have the potential to develop targeted treatments. It’s important to think about PD through this lens, we have a much greater chance of success, as has been demonstrated in oncology, if we can develop the right treatments for the right patients at the right stages of their disease rather than lumping all PD patients together. If you do that, you might lose evidence for an effective therapy since it might only be effective for a subset of the population.
What other gaps need to be filled in order for precision medicine to be effective for PD?
We need to increase our understanding of the molecular contributions to the disease and how the different molecular pathways link to the actual clinical symptomologies of the disease. We don’t have that good direct link between genetic factors, the onset of disease, the progression of disease, and how those genetic factors could impact biological pathways that we can intervene with. We are in the early days of converting this perspective of PD into our ability to develop those types of therapies. We have to do a great amount of research and we have to understand the progression of the disease and the impact of the biological disease on that progression.
One thing that we’re looking on a large scale is a natural history study that looks at the progression of PD symptoms, the biological sampling to look at biological changes and genetic changes, and also utilizing brain imaging to develop links between various biological changes in patient populations and how that impacts the progression. So we can then develop these meaningful subtypes of the disease linked to the underlying biology. That’s the biggest gap we have—can we link meaningful underlying biology to subsets of disease to develop targeted therapies?
In your editorial, you wrote, “Truly transforming PD treatment into a precision approach will require tackling key research and regulatory challenges and the coordinated effort of the entire PD community.” Can you explain this further?
In terms of the regulatory challenges, from the neuroscience and PD perspective, there is a need to better educate ourselves in terms of the neurological community. So this means thinking about PD in a different way where you might have treatments that are targeting very specific sub-populations of the disease and how to go about developing those through clinical trials, and then ultimately go though regulatory approval. We have always looked at PD in the past as lumped together; there are about 1 million PD patients in the world. But now if you look at subsets of the population that may have a very specific genetic risk factor or genetic causal factor, you may be talking about a much smaller patient population.
How would you go about your clinical development paths and regulatory approval in a way that may not have such a large sample size? You might have to develop outcome measures that are more specific to that patient population than some of the general tools we use today. There are precedents for doing that today, but we have not applied those to PD yet. It’s important to bring together all the stakeholders that will be impacted by this, including the academic community with their great understanding, the developers, the regulators, and the patients.
We need to better understand what it means to the patient population that is impacted by the disease. Then we can start developing treatments that are specific in this regard. This is different than what we have done in the past. As you start to develop a therapy and learn about a specific genetic cause of PD, we discover that similar pathways are impacting a greater percentage of the PD population than those who just have that genetic mutation. So how do make that transition from testing the genetic population to a greater percentage of the PD population that may have an impact on that same biological pathway even if they don’t have the genetic mutation and potential to still benefit on that therapy? Lots of data needs to be generated and collaboration is needed, but precedents have been set.
Can you take me through the outcome effect of a precision medicine approach to PD?
I will start with the symptomatic treatment. There is a broad array of available symptomatic treatments for PD that in various ways target the dopamine system. Many PD symptoms are due to loss of dopamine in the brain. We do have available treatments that increase the brain’s ability to make dopamine, we can mimic the function of dopamine, and we have treatments that prevent the brain’s ability to degrade dopamine. But it’s very much a trial-and-error approach right now between the doctor and the patient to find the right cocktail of symptomatic treatment that is best helping that patient at that time and that stage of the disease that he or she is in. So if we had better tools of understanding, either from a clinical characterization of a patient, or a molecular understanding of the disease in that patient, and we had a better way to utilize our existing treatments without going through a trial-and-error approach, you could better target a treatment cocktail to that subset of patients or that one person. You get a better effect of available treatments as a result.
For the longer term, I would say to try to develop specific therapies that are targeting underlying disease processes in the individual to ultimately slow the disease. This is where we would like to go, and I believe strongly that this precision medicine type of approach is the direction we have to go to get to that impact.
What are other next steps?
A big focus of the foundation is trying to leverage this large investment in the study we made called the Parkinson's Progression Markers Initiative (PPMI) that has this very extensive longitudinal data set of PD patients and those at risk for developing the disease. We would like to initiate a series of studies to do deep molecular profiling of these individuals since we already have extensive neuroimaging and clinical data. We would like to really develop that foundation of data we need to segment and subset this population, linking the clinical data to the molecular profiling and characterization as well as the neuroimaging data. Then we can analyze that data to see if we can make meaningful strides in subsetting the population, and identify and push forward towards a more precision characterization of the population, ultimately developing precision medicine approaches. I think we are well positioned to do this.