Defining Parkinson’s Triggers and Catalyzing New Therapies

Why do some people develop Parkinson’s disease (PD) while others do not? The answer involves a complex interplay between genetics, aging, and other factors. Stem cells are fueling our understanding of how brain cells go from being healthy early in life to diseased in old age, as well as catalyzing cell therapies that replace damaged brain cells with healthy ones.

In a recent panel discussion, PD experts Lorenz Studer, MD (Memorial Sloan Kettering Cancer Center), Malin Parmar, PhD (Lund University), Vikram Khurana, MD, PhD (Brigham and Women’s Hospital, Harvard Medical School), and Gist Croft, PhD (The NYSCF Research Institute) discussed how stem cells are helping to address the lack of therapies that can slow, stop, or reverse PD. The discussion was moderated by NYSCF’s Raeka Aiyar, PhD.

What do we know about what causes PD?

PD is caused by degeneration of dopamine-producing neurons in the brain and can lead to symptoms such as tremors, rigidity, slowness of movement, impaired balance or coordination, cognitive decline, pain, and fatigue. Part of the challenge of treating PD is that scientists still do not fully understand what sparks this degeneration.

“When we don’t understand something completely, we call it complex,” noted Dr. Khurana. “Parkinson’s disease is a complex genetic disease. It’s thought to be interrelated between what’s in your genes and what’s in the environment. You might have a genetic vulnerability to Parkinson’s disease, but never get it. You may have a specific mutation that puts you at higher risk of the disease, but you never get that environmental trigger that tips you over the edge.”

What is the status of current PD treatments?

The most common treatment for PD is levodopa (L-dopa). L-dopa is a precursor to dopamine, the neurotransmitter that is depleted in the disease.

“[L-dopa] was revolutionary when it was discovered: patients who were completely frozen were able to walk again. But the unfortunate part of that therapy is that it really works worse and worse as the disease progresses, and it only affects the symptoms from those dopamine cells,” said Dr. Studer.

“There’s also surgical intervention, which is called deep brain stimulation (DBS),” he added. “For DBS, you don’t really do anything directly to dopamine cells, but you try to circumvent them by properly stimulating the brain to carry out their function.”

Patients can also take medications for the non-motor symptoms of PD, but these do not halt or reverse disease progression.

“For those who are patients or caregivers, you will know that this disease has many features that go beyond the motor system,” explained Dr. Khurana. “For example, Parkinson’s affects autonomic features: things that we have no conscious control of in the nervous system like our bladder function, bowel function, or blood pressure regulation. We have very effective medications for [some of] these symptoms, but none of them change the ultimate outcome of the disease.”

Why are so many new therapies failing in clinical trials?

There are still no disease-modifying therapies that can slow, stop, or reverse PD, and new drugs have not been faring well in clinical trials.

“There are human-specific aspects to the biology of diseases like Parkinson’s,” noted Dr. Khurana. “Humans are not mice. That doesn’t mean that we can’t learn anything from mice — we have a lot to learn from different organisms, but there’s certainly evidence growing that aspects of dopamine neuron biology, as well as different subtypes of PD and its genetic and environmental complexities, are quite unique to humans.”

“Sometimes, the first time a drug in a clinical trial sees a relevant human cell is in a human patient,” added Dr. Croft. “Thanks to stem cells, we all believe that it’s now possible to test these drugs on human cells in a disease-relevant model earlier than that.”

How can stem cells help?

Thanks to a Nobel Prize-winning breakthrough, researchers can now ‘turn back the clock’ on our adult cells by taking a sample of skin or blood and creating what we call induced pluripotent stem cells, or ‘iPSCs’ for short.

“The reason that it’s such a breakthrough is that these stem cells are basically avatars of the patients from whom they are derived from: they contain the genetic code of those patients, and they can be converted into any type of cell in the body,” explained Dr. Aiyar. “This can fuel disease research to help to understand how these patients are developing Parkinson’s disease to begin defining triggers for the disease. We can also test drugs in a dish to see which might be able to reverse the effects of the disease and make the cells look more like healthy cells.”

“Stem cells can also help us with diagnostics,” said Dr. Parmar. “I’m working on a couple of projects here in Europe where we [look at patient stem cells to] try to diagnose Parkinson’s disease before the majority of the neurons are dead.”

“We can even look at developing cells for replacement therapy to replace the neurons that are damaged in Parkinson’s disease and put back healthy ones so that the patient can regain the function that they’ve lost,” said Dr. Aiyar.

How do stem cells illuminate how different brain cells factor into PD?

“One of the ways that we study disease using stem cells is to make the disease-relevant cell types. Traditionally, that’s been neurons: they’ve been kind of the stars of the nervous system,” explained Dr. Croft. “But most of the brain is actually made of cells that aren’t neurons called ‘glial cells.’ Increasingly over the past several decades, people have become more aware that these cells have crucial functions, both in maintaining a healthy brain, but also in enacting the processes that are happening in neurodegeneration. My current focus is to expose the role of glial cells in the degenerative process.”

Dr. Croft’s team studies two major types of glial cells: astrocytes and microglia. 

“Astrocytes are the most abundant cells in the brain. They provide energy and chemicals that are required for the survival of all neurons,” said Dr. Croft. 

“The genes that we think are making neurons susceptible to disease also exist in astrocytes, and it looks like they may be functioning or dysfunctioning in similar ways, but because astrocytes do a different job [than neurons], it has a different effect. We believe now that the astrocytes are failing to produce some of the factors that keep neurons alive and that they’re also emitting factors that are damaging to neurons.”

Microglia, the brain’s immune cells, may contribute to PD by causing excessive inflammation.

“Many people have heard about inflammation: if you get a wound or an injury, your body responds by secreting chemicals that draw the immune system in and swell the tissue. The same thing happens in the brain during a blunt injury, but also during neurodegeneration, which makes things worse. What we’re realizing now is that [inflammation] may start much earlier due to hyperactive microglia and this may be driven by [PD risk] genes.”

Thanks to NYSCF’s PD biobank (our collection of cells and clinical data from hundreds of people with different types of PD) and the NYSCF Global Stem Cell Array® (our automated system for creating high quality stem cells at a large scale), Dr. Croft’s team can examine drivers of disease in different brain cell types across genetically diverse groups of patients, enabling unique insights into PD pathology.

“One of the reasons I came here [to NYSCF] is that we have a unique capacity to make thousands of stem cells from thousands of patients,” noted Dr. Croft. “By looking at large cohorts in parallel, we can learn things that we wouldn’t by looking at patients in isolation.”

This is also important for advancing our understanding of how PD affects ethnic minorities, who have been traditionally understudied despite suffering higher mortality rates.

“We can take hundreds of samples and try to interrogate how PD manifests across different ethnic groups,” said Dr. Croft. “It’s no secret or surprise that there’s been a bias in biomedical research, and we’ve now launched an initiative to enrich the breadth of our biobank substantially.”

How can stem cells help us understand PD genetics?

“Stem cells give us a window into individual patients, and what we’re really grappling with in our group is the heterogeneity of Parkinson’s disease,” explained Dr. Khurana. “We don’t have a disease-modifying therapy, and there’s many potential reasons for this, but the one that we are hooked on right now is that Parkinson’s disease may be more than one disease.”

“It’s possible that when we do a clinical trial for Parkinson’s disease, we’re using a single approach that could be working for a subset of those patients, but we would never know because we don’t understand how patients are different from each other,” he continued. “Our lab is integrating genetic information from patients and using stem cells created from those patients to understand whether specific genetic markers may be related to specific subtypes of the disease.”

Dr. Khurana’s group explores genetics by examining changes in the accumulation of a protein that aggregates in PD-affected brains.

“There’s one hallmark characteristic feature of this disease, no matter what subtype you have, and that accumulation of a protein called alpha synuclein,” said Dr. Khurana. “My lab tries to make roadmaps to understand the genetic information that we’re getting from our patients, because we know that protein is deeply involved.”

“We test our hypothesis that certain genes are important in the stem cells that we make from patients. And one of the things that we’ve been very interested in doing is reversing those pathologies in stem cells, and we’ve made some exciting findings there, especially where we can define the mutations in the dish.”

Dr. Khurana is co-founder of a company called Yumanity Therapeutics that recently reported exciting news about a PD drug in Phase 1 clinical trials.

“We discovered that if you change the components of fatty acids [building blocks of fat in our bodies], you can change the way alpha-synuclein sticks to them and alter the abnormal accumulation of that protein,” he explained. “We’re now into Phase 1 clinical trials, and this drug does appear to hit its target, so it is at least doing what we think it should. Next, it needs to be extensively tested to see if it’s effective, but [we’ve hit] a very important first step.”

How can stem cells help us understand the interplay between aging and PD risk?

“Age is a very important risk factor in Parkinson’s disease. In fact, you can easily argue it’s probably the largest risk factor,” said Dr. Studer. “Very rarely does a child get Parkinson’s disease. Even middle-aged people rarely get Parkinson’s disease. Typically it’s 50-80 year-old people that get the disease. And obviously, the question is why?”

“We don’t know for sure [how aging confers PD risk], but we know that many processes in age start changing, not only Parkinson’s disease, but in many other areas of the brain,” he continued. “For example, one very important component is mitochondria, which are structures in the cell that give it energy. Mitochondria will decline in function as we age, and that’s particularly problematic for some cells like dopamine neurons, which need a lot of energy to send their signals.”

“[Other age-related factors] involve how the cell handles proteins like alpha-synuclein. Usually, the body makes sure that proteins get properly produced and then degraded. And in this case, the machinery that’s controlling [this process] doesn’t work as well when you get older, so you can start to get accumulation of ‘trash’ in the cells. Then these proteins have a tendency to actually interact with each other in a way that is harmful.”

“In stem cells, we can artificially trigger age, like putting a movie on fast forward, but for cells,” explained Dr. Studer. “There are diseases, for example, where children are 5 or 10 years old, but they look like they’re 70 years old. So we can take that gene, put it in our cells and try to fast forward age to understand how age-related factors influence the disease.”

“I would argue that aspects of aging may be reversible, and stopping or slowing down the aging process in our cells might be helpful not only for not Parkinson’s disease, but possibly for all neurodegenerative or age-related diseases.”

How can collaborative efforts help uncover drivers of PD?

Drs. Studer, Croft, and Khurana were recently awarded a grant from the Aligning Science Across Parkinson’s (ASAP) Initiative to take a comprehensive look at the interplay between genetics, aging, and different brain cell types underlying individual risk for PD.

The teams will convert stem cells into the different types of brain cells implicated in PD to assess how various combinations of these factors disrupt the function of brain cells using detailed molecular studies, microscopy, genetic manipulations and biochemical measurements — building a computational network model of the factors that cause PD. 

“This ASAP Initiative working with Michael J. Fox Foundation and others has taken a step that many other neurodegenerative disease areas have done and said ‘let’s collaborate,’” remarked Dr. Croft. “It creates a giant community and funds research at a scale which allows us to capitalize on some of the really revolutionary advances in biomedicine.”

How could cell replacement therapies restore healthy function in PD patients?

Dr. Parmar’s work centers on developing cell replacement therapies for PD in which healthy dopamine neurons are transplanted into the brain to restore function.

“In the late eighties and early nineties, I worked at a center where patients were transplanted with dopamine-neuron-forming cells that were collected from the fetal brain,” she recalled. “The problem at the time was the lack of tissue – we needed a renewable source of cells.”

“Stem cells are great because once they’re generated, they divide forever, so you can just make more and more of them. They can also, as mentioned, form any cell type in the body,” she continued.”

For Dr. Parmar’s therapy, stem cells from a donor are turned into dopamine neurons and transplanted into the brains of patients. She hopes that this approach could also one day be leveraged using stem cells created from patients themselves so that patients do not have to undergo immune suppression.

“There’s one donor cell line used for all the patients in that trial. So, these cells aren’t matched to the immune system and the patients undergo immune suppression for the first year,” she noted. “And what’s coming in the future is the possibility to make stem cells, for example, from the patient’s own blood cells or skin cells and then differentiate them into dopamine neurons and transplant them back into the brain [which should avoid the immune suppression].”

A tricky aspect of this approach, however, is ensuring that once new cells are introduced into the brain, they aren’t damaged by the same mechanisms that degrade a patient’s native cells.

“It’s of course very important that the cells that I make to put back in the brain actually do not acquire the disease once they’re transplanted,” remarked Dr. Parmar. “In genetic cases of PD, for example, you probably want to gene edit the cells before you put them back in the brain.”

Scientists could also consider altering cells to make them disease-resistant before transplantation.

“With stem cells, we could potentially endow them with capacities that they don’t naturally have – we could make them resistant to disease or disease-modifying,” said Dr. Parmar. “You could also transplant different kinds of brain cells to try to restore the whole brain circuitry. These therapies are still at the very beginning, but they’re extremely important in driving this field forward.”

Dr. Studer also has a cell replacement therapy for PD about to enter the clinic, the result of a major consortium effort.

“I started on this idea more than 20 years ago, and last December, we finally got the green light from the FDA actually to start the trial here in the US, which is very exciting,” he remarked.

To request more information about Dr. Studer’s clinical trial, contact PDstemcelltrial@mskcc.org.

Why should those affected by PD be optimistic about the future?

“It’s a tremendously exciting time for the basic understanding of the mechanisms of disease and this idea of precision medicine,” said Dr. Croft. 

“I think [what we discussed] are really promising developments,” agreed Dr. Khurana. “We need to understand these diseases better. We need more data. Especially to define subtypes of the disease, we really need a lot of participation from patients and researchers coming together and sharing their data in a timely way.”

“Neurodegeneration of any kind is awful, but progress is happening as fast as it can, and the way to speed up progress is to work together and learn from each other to really bring research to its full potential,” remarked Dr. Parmar.  

“I’m excited on many different levels. I’m excited for the cell therapy, because we’ve waited such a long time [to see that therapy make it to] patients,” added Dr. Studer. “I’m also looking forward to all the things we can learn from stem cells about how the disease works. For many years, Parkinson’s disease or other disorders in the brain were thought to be too hard to fix, and there was a lot of disappointment. I think now, having stem cells, machine learning, and new technology flowing in, there is a lot of hope for making a difference.”