Interview With World-Renowned Movement Disorder Specialist Prof. Anthony E. Lang

Anthony E. Lang MD, is a Professor at the University of Toronto where he holds the Jack Clark Chair for Parkinson’s Disease Research. He is the Director of the Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic and holds the Lily Safra Chair in Movement Disorders at the Toronto Western Hospital, University Health Network. He has published over 650 peer-reviewed papers, over 100 book chapters and is one of the most highly cited investigators in the field of Movement Disorders.

 

The following has been paraphrased from an interview with Prof. Anthony E. Lang on April 20th, 2018.

https://tmrwedition.com/wp-content/uploads/2018/04/lang.wav

(Click here for the full audio version)

---

Toronto has seen a lot of growth in biotechnology fields lately, what effect has this had on neurodegenerative research here?

We have been able to establish useful connections with industry, one of which is with IBM Watson. Our investigators have actively collaborated with them to look for drugs we might be able to re-purpose for Parkinson’s disease. Re-purposing drugs holds a lot of potential because we can get them to people much quicker than we can with new drugs.

You have brought together a really broad team of specialists to work on Parkinson’s disease research here, what are the benefits of this kind of interdisciplinary approach to tackle a problem like PD?

Neurodegenerative diseases are extremely complex, they are not going to be solved by a single approach. You need various experts working together, from those in the lab studying cell and animal models, to people in the clinic caring for patients, and everything in between to effectively translate what we do into humans. You also need people working to understand the disease better by studying epidemiology, pharmacology, imaging, etc. We have been fortunate to bring all of these pieces together here to build one of the best programs in the world.

Which of those puzzle pieces are you most excited about these days?

I regularly tell people that before I quit doing what I do, I want to see us be able to change the natural course of the diseases we are treating. Parkinson’s is clearly a progressive disorder, patients do relatively well in the early stages, but then have a lot of problems later on. I am excited because our understanding of this disease has advanced considerably. We now recognize that even though the cellular processes are complex, there are certain pathogenic proteins (primarily alpha-synuclein) that are critical. Our understanding of how they aggregate and spread through the brain is changing, it really is an interesting time.

Also, seeing the development of treatments designed to alter the aggregation of these proteins is particularly exciting. For example, passive immunization with monoclonal antibodies (antibodies that are made by identical immune cells that are all clones of a unique parent cell) is a very exciting approach. Of course, it could fall flat on its face, but we are hopeful it won’t. Additionally, the models we are using to test new therapies on are improving. The old toxin models did help us advance symptomatic therapies, but did not do much in terms of modifying disease progression. The new synuclein-based models have a lot of promise and the monoclonal antibodies have shown significant impact in those models. I’m excited to see that go forward.

Is there any chance of integrating environmental factors like pesticides or heavy metals into the diagnoses and treatment of this disease?

It is very important to recognize that we are not dealing with a single disease, we are dealing with multiple diseases, that probably have multiple causes, which somehow lead to more or less the same pathogenic process with similar looking symptoms. There are now some epidemiological studies showing signs that certain pesticides are more involved than one might expect, but there are a lot of people with the disease who were never exposed, and also some who were exposed but never got the disease. A lot of people have touted gene-environment interactions as being potential causes of this disease, but we don’t have enough solid proof yet.

However, as we go forward and start to separate patients into their appropriate disease category, we may be able use gene-environment predispositions to help sort the population groups. It will be an important step in identifying the people more likely to respond to a certain therapy. We may find that the first disease modifying therapy only works in 5% of people with PD, then another comes along and works in another 5%. I think it is going to be that kind of incremental success rather than a single home run that applies to a very large proportion of patients with what we now recognize as “Parkinson’s disease”. Environment may play a role, but only in certain individuals, we need to be able to put them into the appropriate disease category before we can really get to effective therapies.

What role, if any, can patients play in basic research?

It is a tough question because it assumes everyone has the same disorder. Perhaps, as we become successful in separating the diseases, it will become easier to answer that question. We want patients involved, we are doing this for them and there is a long history of patients feeling like something is being done to them as opposed to participating and being involved. We have patients involved in steering committees and in determining what kinds of outcomes are important to them in the studies being done. But, at the earliest stages of the basic science, it is hard to see their role at the moment.

Your recent paper titled Disease Modification in Parkinson’s disease states, “…it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past”. Do you think the field is learning from its past mistakes?

If, regardless of how you got PD, synuclein is playing a crucial role in one’s disease, then the monoclonol antibodies might work for broad groups of people, and in which case the mistakes of the past might not repeat themselves. But other approaches will likely only work for smaller groups of people. For example, therapies are being developed that will target patients with specific gene mutations that cause or increase the risk for PD. But this is a relatively small proportion of the population of patients with PD. On the other hand, lacking a clear marker that allows us to “enrich” the population studied, more general approaches, for example, specifically targeting oxidative stress, may only work in a subset of people where that is driving their disease. One non-genetic example of not “lumping” all patients together but selecting patient more likely to benefit is a study using Inosine, designed to increase blood urate levels. This is the only trial to my knowledge that is targeting a subset of patients as you have to have low urate levels to get into the study. All of the other studies going on don’t have any criteria other than having early Parkinson’s.

What we will need to do for future treatments is ensure that we only recruit people enriched for the specific target of the specific treatment in question. We also need to be sure we have evidence we are engaging the target of interest, that is, that the drug is actually doing what we want it to do where we want it to do it (e.g., in the brain).

With some of those attempts to target specific deficiencies, there is more than one trial going on, and each has a slightly different target. What advice would you give to someone deciding which trial to participate in?

It is a difficult problem with no obvious answer but it relates to a concern I have in how we conduct trials in restricted populations and have to decide which trial to prioritize. Do we allow the first drug out of the gate or the company with the biggest pocketbook to decide? This is what we do now, essentially letting the marketplace decide which drugs should be used first and which patients get selected for which trial. Or, should the scientists have some way of controlling this process? I think this is a big concern. How do you screen people for one drug or the other when you have a limited number of people that fit the criteria for entry into these trials? This is an ethical concern that our field needs to consider.

What do you think are the biggest unanswered questions in Parkinson’s disease research?

It relates to what I previously mentioned, since approaching this disease as though it were a homogeneous entity has come up short, we have to figure out how to divide it into separate diseases, while also trying to understand the different mechanisms. How we determine those separations is one of our biggest challenges.

We also need a better understanding of this disease, or diseases, and how it develops. We are beginning to understand the basic mechanisms, but we are still a long way from really knowing how many pieces of the puzzle (puzzles) we are missing and how we can best put all the pieces together. In fact, it’s likely that they fit together differently depending on which version of the puzzle (ie. which type of Parkinson’s disease) we are dealing with. We have a lot of hypotheses but we may find some of them are incorrect.

Click here to learn more about the work of Prof. Anthony E. Lang