The Michael J. Fox Foundation's quest for a cure for Parkinson's disease: an interview with Nicole Polinski

Parkinson's disease (PD) affects an estimated six million people worldwide, a figure that is expected to double by the year 2040 due to an aging population. This progressive movement disorder causes motor symptoms, including slowness of movement, stiffness and resting tremor. However, non-movement symptoms are also common, such as depression, memory or sleep problems and constipation. Parkinson's occurs when brain cells that make dopamine, a chemical that coordinates movement, stop working or die. The mechanism of this neuron loss or dysfunction remains unclear, but researchers believe that Parkinson's is caused by a combination of environmental and genetic factors. Unfortunately, there is currently no cure or therapy to slow or stop the progression of Parkinson's, and current treatments are aimed at relieving both motor and non-motor symptoms. People with Parkinson's urgently need better treatments to improve quality of life and slow or stop disease progression.

Nicole K. Polinski

In this interview, we gain valuable insight into The Michael J. Fox Foundation (MJFF; Box 1) by talking with Dr Nicole Polinski, who is the director of the Preclinical Tools Program at MJFF. She received a BA in Biology from Kalamazoo College and a PhD in Neuroscience from Michigan State University, where she investigated novel gene therapies to treat age-related neurodegenerative diseases, like Parkinson's. At MJFF, Nicole works closely with academic groups, contract research organizations and pharmaceutical partners, to support cutting-edge science and ensure that current Parkinson's disease research aligns with patient needs. Here, she provides an inside look at how the foundation is supporting people with Parkinson's disease and science, and reflects on how patients, patient advocates and researchers can work together in their quest for a cure.

Box 1. The Michael J. Fox Foundation.

The Michael J. Fox Foundation (MJFF) was founded in 2000 by Michael J. Fox, iconic actor, author and advocate, who publicly disclosed his 1991 diagnosis, at age 29, with Parkinson's disease. Since then, MJFF, has become one of the most globally recognized charities for human disease. The foundation has a primary and urgent goal to find a cure for Parkinson's disease and improve patients' quality of life.

They are pursuing this goal by funding and facilitating cutting-edge, interdisciplinary research that prioritizes the patients' unmet needs. To ensure a strategic approach to Parkinson's disease research funding, decisions on allocation are made by an in-house team of formally trained PhDs and business-trained project managers. They also have two distinct research portfolios: the preclinical portfolio and the clinical portfolio. The preclinical portfolio is made up of early-stage projects validating disease targets/pathways and developing drugs in laboratory model systems, such as cells or animals that mimic Parkinson's disease. Many of these projects have been supported by MJFF's Laboratory Resources program and have been successful in gaining further investment to progress towards clinical research stages. In their clinical portfolio, MJFF funds and sponsors clinical trials testing new Parkinson's treatments in patients, with the aim of expanding therapeutic options for the disease.

This research is all led with a strong patient focus, with patients getting involved with programmes, such as Fox Insight that encourages people with Parkinson's and their families to share their experiences, which can help inform the direction of future research. MJFF is also committed to building connections with patients and their families worldwide and organizes Team Fox events to encourage communication between patients, their advocates and researchers. The foundation also offers educational resources and opportunities for patients to participate in research, such as the Parkinson's Progression Markers Initiative, which is the largest longitudinal study of Parkinson's disease. Importantly, MJFF also coordinates and mobilizes advocating activities, to ensure government policy supports Parkinson's research and patients.

Can you provide a brief overview of the research that you did previously, and how this led you in the direction of advocacy?

I have a PhD in neuroscience, and I came from a lab that did research in Parkinson's disease. Specifically, I used viral vectors as a platform to potentially replace or modify different proteins within the brain. My lab had a number of grants from MJFF and, while I was in this lab, I was heavily involved in community outreach and education in neuroscience. I also participated in advocacy events on Capitol Hill, visiting the offices of elected officials to speak to them about the importance of biomedical research and issues that impact the Parkinson's disease community. Following that web of experience, I really wanted to move into a role that was further from the bench and more holistically focused on the needs of the patient community. So that led me to MJFF, where I am Director of the Preclinical Tools Program within our Research Resources Department.

Can you outline what you do on a day-to-day basis and what your main goals are in the foundation?

We have a department within the research team at MJFF that focuses on developing and providing scientists with resources that are needed for their research and can help them translate different biological studies into therapeutic trials. These are pre-competitive resources impacting labs across the field, not just providing one grant to support research in one lab. We're identifying resources that are most needed by researchers, from improvements in imaging reagents and algorithms to analyze data, to the collection of biosamples from patient volunteers. The department that I run is developing preclinical tools and models for researchers. We focus on generating, characterizing and distributing antibodies, proteins, preclinical models, viral vectors, and so on. These are resources that can be used across many labs worldwide, to help understand results between research groups, and help improve replication of results. We make sure that tools are high quality and openly available, so that researchers can access them easily. This means that they don't have to spend a lot of time and money on developing these tools.

[…] understanding some of the non-motor symptoms that are prevalent in [a patient's] life and are decreasing their quality of life can really inform us of what we should be looking for and developing when we're characterizing different experimental models of Parkinson's disease.

How can patient advocates get involved and help to set research priorities in the foundation?

Patients are heavily involved across the board at MJFF. We're always looking to engage with the patient community and their loved ones to understand what their needs are, what their priorities are and what they think we should be focusing on. This is because we are beholden to our donors, and we want to take the research in the direction that they think is best for their needs. They know the disease much better than we do. They let us know what symptoms are the most impactful in their lives and affecting their quality of life. Parkinson's is traditionally seen as a movement disorder but it actually affects the body in general. So, understanding some of the non-motor symptoms that are prevalent in their life and are decreasing their quality of life can really inform us of what we should be looking for and developing when we're characterizing different experimental models of Parkinson's disease. This can open up new avenues into different kinds of treatment strategy or target that we may want to interrogate to alleviate some of these non-motor symptoms, or that may even globally affect Parkinson's disease progression.

Another way we engage the patient community is by reporting back to them, in real time, about the progression of the projects we are funding and what research seems promising. So, we're really trying to actively engage the community back and forth, so that we can inform our research better.

[…] patients and donors who are funding the research at the foundation are partially doing this in the hope of helping their own disease treatment, but more so to help other folks living with the disease or their family members who could potentially develop the disease down the line.

What is the biggest concern for patient advocates?

I think the biggest issue for Parkinson's disease patients right now is that there are no disease-modifying therapies. We only have symptomatic therapies at the moment. The main goal is developing a therapy that can actually slow or stop the progression of the disease, which is especially on the minds of patients. What we've heard more often than not is that patients and donors who are funding the research at the foundation are partially doing this in the hope of helping their own disease treatment, but more so to help other folks living with the disease or their family members who could potentially develop the disease down the line. So really, it's a very altruistic mission from the patient's perspective, and we're really hoping that we can move the needle and find a treatment that can actually slow the process of the disease. In lieu of that, we're focusing on better symptomatic therapies that are more stable in terms of efficacy, dose and route of administration, and would also treat symptoms other than the movement aspects of Parkinson's disease.

Are the researchers that are funded by MJFF generally open to the suggestions from advocates?

Yes, absolutely. At the foundation, we have a couple of different strategies for how we fund projects. Some of these include our open grant call-outs, where labs apply to us with their ideas. In this scenario, we may want to tailor those, but it's usually small changes to, hopefully, improve the success or interpretability of the results. Then we have another programme at the foundation, where we identify gaps in the field and take a strategic approach to address these. To do this, we form a lot of precompetitive consortia composed of different groups across the field, from academia and industry, to address a common issue that everyone is facing and doing it in such a way that the results can be impactful across the field. In that programme, especially, we're really listening to the patients and perspectives from across the field, and then finding research groups who are willing to work with us to address those gaps. We've had such success in this programme. Researchers are very open to working with us to address these common problems because it's impacting everyone and, in the end, it's going to make everyone's research more successful if we're answering the right questions and focusing on the right aspects of the disease. So, these two strategies are how we can set our agenda to face what the patients find most important.

[…] we form a lot of precompetitive consortia composed of different groups across the field, from academia and industry, to address a common issue that everyone is facing and doing it in such a way that the results can be impactful across the field. In that programme, especially, we're really listening to the patients and perspectives from across the field […].

Are there any preclinical studies that you think have been particularly successful in moving into the clinical space?

Two examples come to mind. One target that we've focused on in the foundation is NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), which is related to inflammation. Parkinson's is generally seen as a brain disorder, but more and more evidence is pointing to the fact that systemic inflammation may be impacting Parkinson's disease. So, we've really increased our investment in research on inflammation. There was some really exciting preclinical research showing that NLRP3 is elevated in various experimental models of Parkinson's. Then, different compounds were developed to target and reduce NLRP3 (Gordon et al., 2018). This research is now actually translating into clinical trials, so that was an interesting jump from the bench to the bedside.

Another important area of research that really showcases some of the work we're doing to identify and address field-wide gaps has to do with safety concerns with LRRK2 kinase inhibitors. Mutations in LRRK2 can increase your risk for Parkinson's disease and it is one of the most commonly mutated genes that is linked to the disease. LRRK2 kinase inhibitors are very interesting for their potential to treat that population of patients with the LRRK2 mutation and, also, patients who don't have the mutation but still have increases in LRRK2 kinase activity. However, in our laboratory models we identified some concerning off-target effects that modulate LRRK2 kinase activity in the lung. So, we brought together a pre-competitive consortium focused on understanding these off-target effects, and we published a paper a few years back with the results of that study (Baptista et al., 2020). It was a really good way to bring the community together, around an issue that everyone was concerned about, to help overcome that hurdle.

MJFF has a lot of tools and programmes (Box 1) for the patients, advocates and researchers. Are there any that stand out as particularly helpful or successful?

There's one programme that really marries the patient community with the research community, which is our clinical studies. The Parkinson's Progression Markers Initiative (PPMI) is our longitudinal brain health study, where people with and without Parkinson's are donating their time and biosamples to allow researchers to try to identify novel biomarkers. This aim is to improve diagnosis, disease progression monitoring and disease subtyping, as researchers study the samples and deposit their data back into the PPMI study for others to use. Within this initiative, I think we do a good job of engaging the patient community, as we have regular events where folks who are participating in PPMI can come and meet with the clinical site directors and scientists, to understand how the samples are being used and what advances are being made from them. Beyond this, we do a lot of communication of our results to inform the community of the progress we're making.

In the next five to 10 years, where do you hope that Parkinson's disease research will have progressed to?

I think we're on the cusp of a lot of interesting advances. This is partially due to the invaluable patient biosamples that allow the development of a lot of large datasets. Researchers can use these data to identify new therapeutic targets and new genetic mutations that could be causing Parkinson's disease development or increasing one's risk for Parkinson's disease. These datasets are continuing to develop and we're supplying them to the research community, so they can mine them and use them to inform their research.

I think something else that's really interesting at this stage is the progress that has been made on a new diagnostic test for Parkinson's disease called alpha-synuclein seed amplification assay. Using this assay to test cerebrospinal fluid from people with Parkinson's disease, it has been shown that aggregated synuclein can be used as a diagnostic marker for Parkinson's disease. This is the most interesting result we've seen in this space for a long time. We've seen consistent results across different cohorts, biosample collections and variations on the method (Kang et al., 2019), and the biomarker was validated in our PPMI cohort this year. The next step for this assay is to expand outside of cerebrospinal fluid into less invasive biosamples and work towards a quantitative assay. So I think that's a super-interesting area of research right now that is progressing and it'll be really cool to see where it goes in the next couple of years.

Sometimes, we can have a very myopic view by just focusing on a tiny little aspect, one piece of the puzzle, when – really – taking a step back and seeing the picture as a whole is so important. It opens up so many doors and avenues, and connects you with different researchers and collaborators to whom you may not have thought to reach out to before.

Why do you think researchers should value the voice and views of patients and advocates?

Why are we researching a disease or focusing on disease if there's such a disconnect between the actual experience of the disease and the research? We need to bring those two aspects together, to better understand and inform the direction that the research takes. Sometimes, we can have a very myopic view by just focusing on a tiny little aspect, one piece of the puzzle, when – really – taking a step back and seeing the picture as a whole is so important. It opens up so many doors and avenues, and connects you with different researchers and collaborators to whom you may not have thought to reach out to before. This will lead to the most cutting-edge, breakthrough research within Parkinson's disease but could also impact other diseases. The biggest value for researchers is to understand and view the disease through a different lens that may not be as clear without the patient perspective.

Conclusions

There is an overarching goal in Parkinson's disease research to find a cure or treatments that will slow, stop or reverse the disease. This is desperately required to help people living with this condition, as being offered symptomatic treatments is not enough. MJFF is tackling this problem by strategically approaching it and coordinating global efforts. This will accelerate progress, and maximize time and resources, to ensure we are collectively approaching an effective cure for people with Parkinson's disease. Another hurdle for patients and clinicians is the lengthy process to receive a Parkinson's diagnosis. MJFF's landmark study PPMI is looking to better understand and measure the disease. More information on how the disease starts and progresses not only aids diagnosis but can point to new ways to treat it.

There are many things we can learn from the success of an organisation like MJFF. They demonstrate the importance of listening to patients and their families as this will, ultimately, improve the clinical impact of research. By engaging with these organisations, researchers can be confident that their research is being guided in the right direction. Furthermore, using their tools and resources will ensure high-quality and reproducible research. In a broader aspect, these guiding principles could apply to any human disease, as putting the patient at the center of research efforts will ensure true progress.