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| BRIAN FISKE, PHD |
Editor's Note:
Medscape recently spoke with Brian Fiske, PhD, senior vice president of research programs at the Michael J. Fox Foundation (MJFF), about the latest advances in the understanding and treatment of Parkinson disease (PD).
Medscape: Welcome, Dr Fiske. The MJFF recently held its yearly research conference. What were some of the most promising highlights?
Dr Fiske: A lot of interesting work was discussed at this meeting. The goal was to highlight some of the areas that the MJFF has invested in and where we see really interesting promise. When we invite our grantees to present at this meeting, the goal is to try to build some of that excitement and interest in those project areas. Two talks during the session that focused on disease-modifying therapeutics were of particular interest.
One was from Dr Lars Wahlberg from NsGene; he was talking about his program around delivering the growth factor glial cell line-derived neurotrophic factor (GDNF) to people with PD, which is work he has been doing for quite some time now with us. The idea is packaging GDNF within what he's calling an "encapsulated cell" therapeutic approach; these encapsulated cells will secrete GDNF into the brain of people with PD, with the goal of protecting dopamine neurons.
It's an interesting idea. As a field, we've researched neurotrophic factors before, and there are a lot of challenges and problems that we've faced. I think what's interesting about this approach is that it's a novel twist on how to deliver a growth factor to the brain. He's really gearing up now for potential future human trials, and he's doing some additional work to try to better understand the capabilities of the system. It's really interesting to see the continued progress in that area.
Medscape: What has previous GDNF research in animal models of PD shown?
Dr Fiske: In general, the growth factor field has tried a couple of different approaches, including delivering both GDNF as well as another growth factor, called neurturin, in a variety of different ways. These include infusing the protein directly through a pump mechanism into the brain and also using something more novel, such as gene therapy.
Different companies have tried these approaches; unfortunately, the trial results to date have not been particularly positive, for a lot of reasons that people are still trying to figure out. In general, I think that there is still promise in neurotrophic factor therapeutics if we can do the trials correctly and safely, and in the right people.
Medscape: You described the mechanism as being cellular packets. Are these stem cells that release the growth factor?
Dr Fiske: These are engineered cells that Dr Wahlberg has basically created to produce GDNF. The technology here is that they're encapsulated in a way such that you could put them in the brain, but you could also remove them if you needed to—either for safety reasons or other reasons, to manipulate how you deliver them. It's like using the pump that infuses into the brain: If need be, you can turn off the pump. Gene therapy is obviously more of a permanent production, so if you put a gene into the brain, it will continue to produce GDNF. This was sort of a compromise between the two.
The encapsulation approach also helps to ensure that the cells are protected from possible immune rejection by the patient, which is obviously another important concern.
Medscape: So a neurosurgeon would place these packets in the substantia nigra or some other region of interest?
Dr Fiske: Yes, and then it would produce GDNF, secreting it from these cells and acting as neurotrophic support for the brain.
Identifying Genetic Targets for Drug Development
Medscape: That's fascinating. What other research presented at the meeting shows particular promise, in your opinion?
Dr Fiske: I think the other interesting highlight was around a genetic target for PD. There is a gene called leucine-rich repeat kinase 2 (LRRK2); in about 2004, some of the mutations within the gene were first discovered to be associated with PD. Since that time, people have really become excited about this target for a few reasons. One is because of the genetics; there is a strong genetic link to PD.
But also, the gene encodes for a type of protein called a kinase, and because of that, drug companies have become very interested in developing drugs that target it. They are very familiar with making drugs against kinases from other fields, such as oncology. Because of the really strong genetics and the compelling biological function of the protein, it's had a robust response from drug-makers working in the PD field.
What was interesting about the presentation at the conference—which was presented by one of our research staff members, Dr Marco Baptista—was a lot of work that we've been doing in the past year or so, looking at the potential safety of LRRK2-targeted targeted drugs. It started about a year or two ago, when some initial data came out showing that Genentech's version of an LRRK2 drug, when delivered into nonhuman primates, was showing some cellular abnormalities in lung tissue. We very quickly worked with them to try to verify that finding, to be sure that we could replicate it and understand it to determine whether it was really true or not. We've been working to verify those findings, first with Genentech and then ultimately with other companies.
Marco presented the outcomes of some of these studies, looking to demonstrate whether or not we can see this lung cellular abnormality in primates treated with LRRK2 inhibitors. We've also been trying to better understand what this could actually mean. For example, is it causing any functional changes in the lung, and are there detrimental effects? So far, we don't see any functional impact on the lung tissue at all, and the cellular abnormality is reversible when the drug is stopped, so our sense is that many companies will continue to pursue their LRRK2 inhibitor programs regardless of this potential finding. We'll need to decide in future clinical trials whether we need to put in particular safety measures to look for lung function changes in people.
Medscape: How far off do you think human trials of LRRK2 inhibitors are?
Dr Fiske: It's hard to say. I think it really depends on a variety of factors. It's been relatively easy to make LRRK2 drugs because of the chemical knowledge people already have around this type of protein and drug target. I think the real challenges are more around the trials.
Obviously, if you're going to be moving into a clinical trial, presumably you're going to want to start first with people who carry the LRRK2 mutation. Making sure that we could actually find enough of those people, and at the right stage of PD, to actually be able to do this type of trial is one logistical challenge.
Another important issue is what types of biomarkers you would want to measure in these individuals, to know that your drug is actually affecting not only PD-relevant biology but also LRRK2-relevant biology specifically. I think we will see some of these drugs start moving into the clinic in the next couple of years, on the basis of our initial forecasting.
Using Biomarkers in Predictive Modeling for PD
Medscape: How about biomarkers? Was there anything new this year at the conference?
Dr Fiske: Yes, there was some interesting work around biomarkers. Obviously, this has been a big effort for the MJFF, and we've invested quite heavily in this area—in particular with regard to a large study, the Parkinson's Progression Markers Initiative (PPMI). Now that the study has been ongoing for 5 years, we're starting to get really meaningful data out of it.
One presentation that I think was particularly interesting was from Dr Andrew Singleton at the National Institute on Aging, which is part of the National Institutes of Health. He has been utilizing some of the data from PPMI, along with other data, to devise predictive models that could be used to help determine whether someone is at risk for PD. He's looking at a combination of genetics and some clinical features that basically allow you to distinguish people with PD from those without PD. The idea is that you ultimately predict whether someone might be at high risk for getting PD. These data were actually published in Lancet Neurology this year.[1]
A nice feature of the PPMI study is that the data that we collect are made available in real time, so people can have access to them as soon as we're able to get them out through the distribution mechanisms. People are then able to do these types of studies far more easily.
The Prion Hypothesis: An Update
Medscape: How about the idea that PD might be a prion-like disorder? Have there been any recent updates in the field here?
Dr Fiske: This continues to be an interesting area. What's most exciting about alpha-synuclein in the therapeutic space right now is that we have multiple companies conducting clinical trials with various alpha-synuclein–based therapeutics: AFFiRiS, Prothena, Biogen, and Neuropore are developing therapeutic programs around alpha-synuclein in the clinic.
The prion hypothesis is very interesting, but whether it will necessarily affect existing therapeutic approaches is unclear. Most of these approaches are not targeting the actual mechanism of the alpha-synuclein spread, but rather trying to target alpha-synuclein directly and lower it or get rid of it. Hence, we don't think that answering the question about whether alpha-synuclein spreads in a prion-like mechanism is necessarily going to affect current therapy, but you never know.
Medscape: Do you think that the prion theory could be the unifying factor between PD and other neurodegenerative disorders, including Alzheimer disease?
Dr Fiske: I think it's an interesting question to ask. And I do think that the idea of an abnormal protein causing other proteins to become abnormal and spreading across the brain could potentially be a common thread underlying a number of neurodegenerative diseases. I think it is something that we continue to monitor very closely. Obviously, if that is true, it gives you some common areas and ways to target those kinds of mechanisms that could then have an impact beyond PD.
Generally, in the field of neurodegenerative research, people are starting to home in on these kinds of common biological pathways—how proteins are handled and distributed and gotten rid of in cells, and also how bioenergetic mitochondrial dysfunction might be involved. I think as we understand more about these diseases, we may start to realize that there might be more similarities than differences.
Medscape: Are there any final highlights from the research conference you'd like to share?
New Formulations, New Technologies
Dr Fiske: Dr Warren Olanow from Mount Sinai Hospital discussed the plethora of options that are now coming to patients in terms of different ways to deliver dopamine therapeutics. In the past, it's always been just the traditional dopamine approaches (eg, Sinemet® [carbidopa/levodopa]), and then some of the dopamine agonist drugs that are available. We're now starting to see additional types of drugs becoming available, including intestinal gels (Duopa™) and extended-release formulations (Rytary™), for example.
Dr Ray Dorsey from the University of Rochester discussed another interesting area: the growing trend to use different technologies in PD care, in particular wearable devices and smartphones. We're investing in this area ourselves and trying to collect data in novel innovative ways from people with the disease, so that we can better understand their day-to-day experience. I think we will continue to see this type of movement in the field as we better understand the technologies we have, and what we do ultimately with the data they can supply.
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