On Wednesday, September 30, Jeff Conn, PhD, announced at The Michael J. Fox Foundation’s third annual PD Therapeutics Conference that his MJFF-funded team at Vanderbilt Medical Center had hit a major milestone in its pursuit of a new class of glutamate-based therapies for Parkinson’s disease. The Foundation spoke to him about what his team has achieved and the possible implications for Parkinson’s patients.

NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.


MJFF: When we talk about ways to improve treatments for PD and create new ones, we are usually talking about dopamine — how to restore function in dead or diseased dopamine cells and increase levels of dopamine in the brain. As a PD researcher, why are you interested in glutamate? Can you explain how it might lead to a treatment that could transform patients’ lives?

Jeff Conn: Sure. This approach really started many years ago, with discussions surrounding some evidence that it might be possible to pharmacologically accomplish the same thing that’s currently done with deep brain stimulation (DBS), pallidotomy or other surgical approaches. As we know, those surgical techniques are used in very advanced patients who are no longer fully responsive to levodopa and other dopamine replacement therapies. These patients have problems with dyskinesias as well as other issues, like the wearing-off effects and on/off cycling in late-stage PD. And surgical techniques are used only in very advanced patients, because patients are considered candidates for surgery only after they come to a point where they’re no longer effectively treated with levodopa and related therapies.

So clearly, there would be a major advantage to a pharmacological therapy that could provide the same therapeutic benefit as a surgery. All patients would be able to take that medicine. They wouldn’t have to wait to become less responsive to a drug in order to qualify for a surgery program. Additionally, patients could begin on the medicine early in treatment, which could theoretically mean avoiding altogether the problems that develop with chronic levodopa and dopamine agonist therapies.

That is the concept that started this program. From there, instead of just taking that idea and looking for drugs or drug-like molecules that were available at the time, we decided to take a more methodical approach in thinking about the brain circuits that are altered in Parkinson’s surgeries. We wanted to go in and systematically identify targets that had not been thought of before, purely based on our understanding of what happens with those surgeries — and then specifically go after those targets.

So our progress now is the culmination of over 10 years of work that started with just trying to identify those targets back in the 1990s, and then, once they were identified, starting the process of getting the first molecules to see whether it seemed to be a viable approach. And now we are at the point of having molecules that are moving well along the path toward novel therapeutic agents.

MJFF: Now that we understand a little bit more about glutamate’s possible therapeutic potential in PD, please explain more about the specific ultimate goals of your LEAPS award. What kind of treatment would this be?

JC: Ideally, this would be an orally administered drug. It is possible that such a compound would be effective enough to be used as a stand-alone treatment in patients, although we may find that it is more beneficial when used in combination with levodopa therapy. In the latter case, one goal would be to reduce the dosage of levodopa required to control symptoms with the hope lower levodopa levels would reduce treatment-related symptoms such as dyskinesias or behavioral disturbances.

MJFF: So — we’re exploring glutamate because we want to bypass the negative side effects of dopamine-based therapies. But is your team testing for the possibility that there may be unexpected side effects to glutamate-based therapies too?

JC: This is a very important issue. With any new drug treatment or target, there is always the possibility of adverse effects that will be different from existing therapies. With the glutamate receptors we are targeting, we can’t say for certain at this point; based on the data that we’ve had so far, we don’t see major problems. But let me expand on that a little bit.

Glutamate is a major transmitter in every brain circuit. It is everywhere in the brain, and it’s critical for all brain functions. If you dramatically alter glutamate transmission in a way that affects all brain regions, then you are very likely to have adverse effects. That’s been a problem for some previous glutamate-based therapies.

In our case, instead of going after the major glutamate receptors that are involved in many brain regions — one example would be NMDA receptors, which have been looked at experimentally for Parkinson’s in the past — we identified a specific glutamate receptor subtype called mGluR4. This receptor is present at a key synapse in the basal ganglia motor circuit impacted by Parkinson’s surgeries, but it is not widely distributed in other brain regions; nor is it present, for the most part, in peripheral tissues. Although it’s not accurate to say that it is present solely in the part of the brain we’re interested in, its distribution is very limited. So, by targeting this specific receptor, we believe we can limit adverse effects and that we’ll be looking at a much more favorable profile.

The other thing we’ve done to decrease the likelihood of adverse effects is to take a very subtle approach to manipulating these receptors. You can liken it to a dimmer switch on a light in your home, where you can turn up the gain of the receptor and its activity, or turn it down, without completely activating it or shutting it off. It’s another safeguard we’ve built into our program.

Having said that, we don’t know for certain what side effects will be observed — and we ultimately won’t know until this is tested in humans. In my mind, it is always possible that modulating the basal ganglia motor circuit could have unanticipated motor side effects, and there could even be other things that we aren’t thinking about right now that occur as we get further into pre-clinical experiments.

MJFF: Please tell us about the specific milestone you have now achieved.

JC: The big step forward that this milestone represents is that we have developed two structurally related molecules to the point where they are systemically active. “Systemically active” means that when we administer these molecules in a pre-clinical model, they distribute into the brain and go to all the right places. That has allowed us, for the first time, to verify that when these molecules are applied in a relevant pre-clinical model of PD, they have statistically significant anti-parkinsonian effects. Most notably, in severely parkinsonian models, these compounds reduce akinesia (“freezing”) and rigidity. We are now examining the effects of chronic dosing over periods of weeks and effects on more subtle aspects of motor function in less severely parkinsonian models.

Now I’d like to put this in the context of our larger project. In this type of effort, you start with a vast library of compounds to screen just to get a foot in the door. In our case, the library was 160,000 compounds. And a great deal of work had already been done even by the time we began looking at those 160,000 molecules. We knew we had identified the mGluR4 receptor; we knew we wanted molecules to interact with this receptor. But we also knew that we wanted to develop them to the point where they could be used at drugs. We screened the libraries and searched with informatics techniques to find the molecules with the qualities we wanted. We needed them to have a high level of activity at the target receptor; to be able to be swallowed as a pill; to be absorbed into the body and distributed into the brain and get to the part of the brain that’s important; not to cause toxicity or drug interactions.

And even once we find them, they are far from being drugs. It’s really not just searching through compounds and knowing there’s a drug in there somewhere — there’s not. But what we get from the screening process is a starting point for a major chemistry program, which is also a high-level engineering project, to engineer the molecules to have all the properties needed to eventually be packaged in the form of a medicine, and prescribed so that a patient can swallow the medicine as a pill and have a therapeutic effect.

In this project, we started with molecules that had the activity we wanted, but the activity was very weak. They also had activity at other kinds of enzymes and receptors that would be problematic. They didn’t get into the brain and they didn’t have any of the properties that you would need in a drug. So we’ve been in this major chemistry effort for the initial period of our LEAPS project, up to now, working to engineer these molecules to the point where they would have all the necessary properties. And we’re still not at the point where we have something we can take into humans to test, and we have a ways to go before we get to that.

MJFF: What are the next steps for your team?

JC: The next step is to now take these molecules and look at them in a much more rigorous way across multiple pre-clinical models. We need to look at the effects of chronic dosing, which we’ve not yet been able to do and which is obviously critical for Parkinson’s patients. We need to look for possible toxicity that we may not be expecting. What’s truly exciting is that we are now at the point where we can begin to systematically do this testing, which is the next phase of pre-clinical testing on the path toward first-in-human trials.

MJFF: Can you make an educated guess about the time horizon to a possible clinical trial?

JC: Obviously there are never any guarantees, and it’s always important to caveat discussions of possible clinical trials and temper our anticipated timelines with a great deal of caution. But at this point, we do have some clear timelines that we are shooting for.

Our goal is to have a compound with the properties required to advance toward clinical testing by the end of 2010. That’s what we call a pre-clinical development candidate, and there is a very well-defined set of criteria for molecules before they reach that stage. If we hit that goal, the molecules would go into a very standard set of studies required by the FDA, called Investigational New Drug (IND)-enabling studies. IND approval is required to initiate clinical testing. IND-enabling studies typically take about a year. If we’re successful, those studies would wrap up around the end of 2011. That would mean that first-in-human dosing in a Phase 1 clinical trial, most likely in a small group of healthy individuals, would be on track for the first quarter of 2012. That Phase 1 study typically takes about a year, and if successful, we would be looking at testing in Parkinson’s patients by 2013.

It is vitally important to remember that these are goals, and there are often setbacks on the way to achieving goals. While I am cautiously optimistic at this point, I have been in situations like this one before, as have my colleagues in drug development and all Parkinson’s patients. All of us have had to cope with disappointment many times, even when a program was going very well and there seemed to be great call for optimism. So I urge patients — and the PD community at large — to look on these outcomes, as promising as they are, with caution.

MJFF: Bearing those caveats in mind, would you still say that you are excited about the potential of glutamate to lead to a next-generation therapy for Parkinson’s?

JC: Yes. Of course you hear caution in my tone as soon as I start talking about timelines. But we are very excited. This is an approach that I really believe in. Out of all the things we’ve worked on, this is one where, if we can develop a molecule that has the right properties and does not have toxicity, we really believe that this has an opportunity to have a major impact for Parkinson’s patients. Nothing could be more exciting than that. If we are successful, the impact on the lives of so many people — nothing could be more gratifying than that.