Novel therapeutic targets for Parkinson’s disease: an interview with Patrik Brundin

Written by Sharon Salt, Editor

Patrik Brundin (MD, PhD) is originally from Sweden and has spent around 30 years at Lund University (Sweden). Currently, he is the Director of the Center for Neurodegenerative Science at the Van Andel Institute (MI, USA). Patrik is also one of the top cited researchers in the field of neuroscience with more than 300 publications on Parkinson’s’ disease and related topics.

In this interview, Patrik speaks to us about what inspired him to work in in the Parkinson’s research field. He also tells us more about his talk on novel therapeutic targets for Parkinson’s disease and how he’s extremely optimistic for the future direction of the field.

1.What is your current research focus and what inspired you to work in this area?

Wow, this is a big question! I’ll start with the last part of the question and work chronologically. My dad was diagnosed with Parkinson’s disease when I was 12 years old and this is what really inspired me. I had already decided at the age of 17 that this was something I wanted to work on. I did the International Baccalaureate in high school and we were given the option to pick a topic to do our extended essay on, and I chose Parkinson’s disease. Since then, I never looked back really.

You could say that I’m still working on this extended essay. Initially, I spent around 20 or 25 years very much focused on brain repair and developing brain cell transplantation techniques. My thesis work involved the clinical trials we did in Sweden with brain cell transplants, and we serendipitously found Lewy bodies in some of these transplanted cells in patients who had died 10–16 years after having surgery. Consequently, this led me to focus more on understanding how this phenomenon could develop. Thus, my focus today is on disease mechanisms and disease-modifying drugs.

I also continue to have an interest in brain cell transplantation, so I co-chair a scientific advisory board for a company called Fujifilm Cellular Dynamics, Inc. (WI, USA) that is planning to do clinical trials with induced pluripotent stem cell-derived neurons.

2.You presented a talk at the Alzheimer’s & Parkinson’s Disease Congress (26–31 March 2019, Lisbon, Portugal) on novel therapeutic targets for Parkinson’s disease – could you provide us with a brief overview about your talk?

Yes, I did, and you tweeted about it! I was asked to present novel targets in the space of 13–14 minutes and it’s very difficult to present more than one target in this amount of time. I chose to present work that was almost exclusively done by others but it’s an area I’m very interested in.

…there may have been positive effects on mood, but because of the trial design the researchers only reported on all non-motor outcomes together – strictly speaking they were not allowed to look separately at mood.”

My talk was based on the idea that one can modify metabolism in the Parkinson’s brain by targeting the GLP-1 receptor. This receptor has been targeted for Type 2 diabetes and there are available drugs, notably exenatide, which lower blood glucose levels. It turns out that in animal models of Parkinson’s, exenatide can also reduce pathology and it has been tested clinically. I described the clinical trials that have been carried out, which were double-blind, placebo-controlled trials carried out by Tom Foltynie at University College London (UK) and his group approximately 1.5 years ago demonstrating that there is some modification of disease progress following exenatide treatment.

There are all sorts of little technical details that I didn’t go into in my talk but Phase II trials are only Phase II trials, so now it’s time for the Phase III trial that can provide more definitive answers regarding the effectiveness of exenatide in Parkinson’s. Post-hoc analyses of the published Phase II trial suggest that slightly younger patients with tremor-dominant disease and shorter disease duration might have done particularly well on the drug. I say might because they are not statistically significant findings. Furthermore, there may have been positive effects on mood, but because of the trial design the researchers only reported on all non-motor outcomes together – strictly speaking they were not allowed to look separately at mood.

Thus, this all suggests that it’s worth going forward to a Phase III trial and perhaps focusing on younger patients and having one of the pre-defined outcomes focused on changes in mood. Many trials with GLP-1 agonists are either underway or planned and hopefully the Phase III trial will happen soon.

3.In your opinion, what are some of the key hurdles to be overcome in this field?

Firstly, despite an estimated (according to Alberto Espay, University of Cincinnati, OH, USA) US$23 billion having been spent by industry in trying to modify disease, nothing works. Therefore, the first hurdle is lack of confidence in the field amongst both scientists and investors.

The second hurdle is choosing the right type of target because there are so many mechanisms that are involved. Perhaps we need to go away from the traditional notion that there is only one drug target and one molecular pathway that is relevant to Parkinson’s disease, and each trial can only address one part of the pathogenic process. Maybe we do need what some people refer to as ‘dirtier drugs’ – drugs that are promiscuous and affect multiple molecules or multiple cells.

Additionally, another hurdle is designing trials where you recruit the right group of patients, and this was discussed by others in the session I spoke in. Maybe precision medicine trials, where patients are stratified according to, for example, clinical features or genetic profiles, will be more successful by reducing variance.

The next hurdle is having good measures for target engagement, which I mentioned briefly in my talk and objective markers for disease progression.

There are lots of hurdles to be overcome. With all the setbacks, one might wonder why we even try sometimes. Nevertheless, believe it or not, I’m very optimistic that there will be something that will work one day. Never in history have we known as much about Parkinson’s disease as we do today, so I’m quite hopeful.

4.Lastly, where do you anticipate the field will be in 5–10 years’ time?

One thing I am certain of is that the current definition of Parkinson’s disease will have to be revised and refined.”

I really do think in 10 years from now we will have a couple drugs, or biologics, that are approved for disease modification in Parkinson’s disease. I’m going to stick my neck out and say I think this will happen.

I also believe that, on a broader picture, we will no longer talk about Parkinson’s disease as one disease – we will have reached a consensus on how to subgroup individuals. Some people take the extreme view that every individual is so specific that we should have a molecular fingerprint, but I think we will still end up having groups and clusters of people that share several features with each other. Perhaps we will end up calling these clusters Parkinson’s disease type 1, 2, 3 etc. One thing I am certain of is that the current definition of Parkinson’s disease will have to be revised and refined.

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The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.