Genetic Forms of Parkinson Disease May Hold Most Potential for Targeted Treatment

Ignacio Mata, PhD

Parkinson disease (PD) can be caused, in different cases, by a number of complex factors including genetics, lifestyle, environmental factors, and other factors that may not even be known. As such, developing new treatments for PD is highly complex, as well, and, unfortunately, not much progress has been made in the past few decades.

CGTLive^® recently reached out to Ignacio Mata, PhD, an associate professor of neurology at the Cleveland Clinic Lerner Institute, to learn more about the current state of PD research, and where more work is needed. Mata discussed the importance of detecting the disease in patients earlier and the potential of slowing or stopping disease progression in patients with genetic forms of PD via targeted approaches.

CGTLive: Can you discuss the current landscape of care for PD and the unmet needs that remain for this patient population?

Ignacio Mata, PhD: So full disclosure, I'm not a doctor. I'm a PhD, obviously, so I do research in genetics, mostly. So, I don't deal with patients on the day-to-day. But, PD is a very complex disease. I think neurologists will agree that it is very complex from the symptoms' point of view. It's also very complex from the biology point of view, right? There are at least 20-some genes that cause familial forms of PD, there are about 100 additional genes that are risk factors for PD, and then in addition to that, you have all the environment, lifestyle, and other factors. It makes for a very complex disease to study and a very complex disease to treat.

We've had the same drug for over 2 or 3 decades now, which is great to treat the symptoms. Obviously, there are some issues with the current treatments, but they can give good quality of life to patients, especially for 5 to 10 years, depending on the patient. There are also surgical procedures, like deep brain stimulation, that can also be used once the drugs stop working as well as they should. But we don't have any treatment for slowing or stopping the disease. I think that has been the major focus in a lot of the research that people in the field are doing. There's been a lot of clinical trials with many different types of therapies that have been used. So far, we haven't been successful, which is very similar to what is happening with the Alzheimer disease (AD) field, as well.

What could be driving that lack of success in introducing novel disease-modifying therapies?

Again, I think part of it is due to the complexity of the disease. I think part of it is also that the disease when it appears as we recognize it in the case of PD, is usually with the motor symptoms. When it appears, more than 80% of the dopaminergic neurons are already gone. So the disease has been going on maybe 10, 15, or 20 years already in the patients. So by the time they show up in the clinic, the disease is very progressed. Although it looks like the symptoms are mild at the beginning, biologically it has been going on for a while.

So another hypothesis that has been thrown out there is that maybe we're catching these people too late. We don't have any biomarkers, currently. I think there are some in the pipeline with α-synuclein aggregation that maybe will allow us to identify people before they develop the symptoms. In other people, I think that the therapies that we're trying, especially with those trying to avoid synuclein aggregation, might not be the correct ones. I think the same thing is true for AD, as well. I think for those 2 diseases, some people in the field believe that maybe the hypothesis is incorrect, and maybe we should be providing normal α-synuclein, instead of trying to avoid aggregation, as that might be the byproduct of all the damage that is happening. So, there are a lot of different hypotheses that are going around.

I think having ongoing clinical trials is important. I think the closest that we are right now to something that may slow or stop the progression are those that are targeted for people that have a genetic form of PD, where the biology is at least mostly understood and is caused in some of those cases by 1 single variant. [W]e can understand what is happening biologically and we can try to compensate for what the deficit is. So I think there's definitely a huge need for new therapies, and especially those that help us to slow down or stop the progression.

Transcript edited for clarity.