A New Frontier in Alzheimer Disease

Evan Y. Snyder, MD, PhD; Stuart Lipton, MD, PhD


July 19, 2011

Editorial Collaboration

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Evan Y. Snyder, MD, PhD: Hi, I'm Dr. Evan Snyder, Professor at Sanford-Burnham Medical Research Institute. Welcome to Developments to Watch from Sanford-Burnham and Medscape.

Joining me today is my colleague. Dr. Stuart Lipton, Professor and Director of Neurodegenerative Disease Research and a practicing neurologist.

Today's program will focus on key research addressing the health consequences of neurodegeneration in Alzheimer disease, and how this research will affect clinical practice. Thanks for joining us, Stuart.

The Development of Memantine

Now, of the many areas of research at Sanford-Burnham that have made an impact on clinical practice, I think it's no secret that memantine for Alzheimer disease ranks very high. It's very recognizable among patients and clinicians. You're well known as the developer of memantine. How did you come to develop this drug and how does it differ from other kinds of drugs for Alzheimer disease?

Stuart Lipton, MD, PhD: Well, Evan, thanks for having me here.

Memantine is an interesting drug because it was repurposed. It was actually an anti-influenza drug, and this is a very important fact because many drugs used in the brain fail because they're not safe. So taking a drug that's already used for something else and discovering how it works in the brain really saves years of drug development.

Now, it's not a cure, there are no cures for Alzheimer disease, we're all working very hard on such drugs. But up until now, we've used symptomatic treatment with drugs that increase acetylcholine in the brain, one of the neurotransmitters that's important in memory. Memantine works fundamentally different. It works on another neurotransmitter called glutamate. Glutamate is the major neurotransmitter that's important in communication between nerve cells. We and others have felt that glutamate signaling is disrupted, which can overexcite cells and injure them, injure their synaptic connections, and eventually cause the cells to die. Memantine prevents that.[1,2]

I really discovered it in a sense by serendipity. I was on a sabbatical at the Max-Planck-Institut für Hirnforschung for Brain Research in Frankfurt, Germany, and a colleague of mine was working on the drug there. As I said, it was used for influenza, and it was also used for Parkinson disease, although no one knew exactly how it worked. And we were able to discover a mechanism of action for the drug.

Elucidating the Mechanism of Action of Memantine

The mechanism is interesting, because the drug doesn't work that well. What I mean by that is that it's a very low affinity drug. It doesn't stick well to the glutamate receptors. But the key point about this drug is that it only works when you need it to work.

Glutamate, the major transmitter in the brain, binds to its receptor and that opens a channel, a physical pore in the membrane. That's important. It's important for just talking to one another, for our memories. You can't block that, although many in big pharma, many pharmaceutical companies try to produce drugs that would block that. Too many side effects.

What this drug does, is it only blocks that pore. It goes into the pore, binds there, only when those channels are excessively activated. Then the key thing about memantine is that, somehow, a property of a drug, it knows to come back out when things are normal. Perhaps we can show you this on a slide.

Dr. Snyder: A slide would be great. Thanks.

Dr. Lipton: As you can see on this illustration, on the left side, calcium is entering through this channel I described that's coupled to glutamate. Calcium is normally a good thing -- you need ions to flow in for normal neurotransmission. But if there is too much calcium, you generate free radicals and injury to the brain.

Memantine kind of works like as shown on the right side, a cork in a wine bottle, or the volume on your television set. Just like my voice is too loud now, when there's too much flow of calcium through the channel, memantine moves in and blocks it, as shown here. So you can't have excessive calcium coming in.

Now, interestingly, this mode of action has a technical term, it's called uncompetitive [inhibition]. And then, as I mentioned, memantine knows to come out when things are normal and has a fast off-rate. No one would ever remember this, and then I was writing a review for Nature a few years ago, and the editor said you need to come up with a mnemonic and I realized a mnemonic was for "uncompetitive fast off rate," -- UFO. So we call these UFO drugs.

If you didn't read it in Nature, you probably saw it in one of these journals because it did get quite a lot of press when it was approved by the US Food and Drug Administration (FDA).

I should also disclose this work was done while I was at Harvard Medical School, and they received royalties from Forest Laboratories in New York, and I share in those royalties.

Targeting Neurodegeneration

Dr. Snyder: It's very interesting that we now have to have a more sophisticated view of the use of drugs. It's not whether something's on or off, but exactly how you modulate various kinds of activities. So this probably has implications not just for Alzheimer disease, but for a whole range of diseases, including neurodegenerative diseases.

In Alzheimer disease, why is focusing on neurodegeneration so important? Why should we be focusing on that? Why should the average clinician be concerned about your studies in this area?

Dr. Lipton: What we now know about Alzheimer disease, Evan, is that it's a disease of the synapse, the connections between nerve cells. The only neuropathologic correlate to your cognitive decline -- it's not plaques and tangles, which we'll talk about in a moment, it's a loss of synapses, so we need to protect the synapse.

Memantine is not perfect in this area. There are newer drugs coming down the pike, which we'll talk about in a moment, that are better. But we need to protect that synapse because that's what's injured.

Now, up until now, what we thought is important in Alzheimer disease -- and it is -- are 2 proteins called amyloid beta protein or Abeta, which misfolds; and tau protein, which gets hyperphosphorylated (too many phosphate groups on it) and it misfolds.[3]

There's a panoply of work in this area trying to block those abnormal proteins and that's important and we need those drugs. But, unfortunately, up to now, those drugs have had too many side effects. There are ongoing clinical trials, and we're all hopeful that breakthroughs will come.

I think where our group and now others have shown is how this glutamate in normal signaling is disrupted by amyloid and tau. So we're actually going after a downstream effect that seems to be more approachable because we've learned how, exactly as you said, to interfere with it in kind of a suave or soft way, not a sledgehammer way like most drugs. And by doing this, by just modulating the activity, we're able to begin to protect those synapses.

Now, this is true in Alzheimer disease, it's probably true in many neurodegenerative diseases; it's just that synapses in different areas of the brain in different diseases may be affected.

Dr. Snyder: So you've actually got onto a very important aspect. There are many ways that the world of research and the world of medicine think about diseases. Some of it is stopping the degenerative process, or, in Alzheimer disease, getting rid of kind of the tombstones of disease like the tangles and things of that sort. Your approach has always been for many years to be neuroprotection, which is a very interesting way of looking at these diseases.

Why is this, why is neuroprotection such an important way of approaching these diseases and why should clinicians be thinking about this? I imagine this also means that we need to start thinking and diagnosing these diseases even earlier. So why is neuroprotection so important?

Dr. Lipton: That's exactly right. By the time we diagnose Alzheimer disease or Parkinson disease or glaucoma in the eye, often 80% of the nerve cells are already lost.[4] We need biomarkers to look much earlier and then begin earlier treatments. For that we need better treatments. As I mentioned, memantine or the earlier drugs that increase acetylcholine really only offer symptomatic relief. Memantine is just beginning to get at neuroprotection. We're developing newer drugs that seem to be better in this regard but we have to protect those synapses. As I said, it's the only correlate with cognitive decline.

Dr. Snyder: Well, as you know, I'm a developmental neurobiologist in addition to being a child neurologist, and we know how hard it is to create all this very elegant circuitry to begin with. It's clearly much -- not easier, but at least more tractable to protect what you have than trying to completely recreate what nature gave you to begin with, so that is a very important way of looking at these diseases in general.

Next Steps in Neurodegeneration Research

I guess now we should think about what is on the horizon, what will be important that will be changing clinical practice in the future. So if you had a crystal ball, where do you think research in this area will be moving?

Dr. Lipton: Well, many groups are attacking these proteins I mentioned, Abeta and tau. We're still attacking a synapse to protect it. As I said, recent work by our group and others have shown how Abeta, tau, and glutamate all tie in together.

Now, the existing drug memantine, as I mentioned, is nowhere near a cure. What can it do? Well, when they broke the phase 3 trial, the pivotal trial for FDA approval, they found that some patients who weren't recognizing their loved ones began to recognize them again.[5] And if you're a caregiver, and we've done this in my own family, that's a big deal. But it's not a cure. We need people to get their memory back or to prevent their memory loss, and one way that we personally have gone about this is to try to improve memantine. We've made derivatives of memantine that actually do protect the synapse, they prevent synapse from being lost, from dropping out. One series of drugs are called nitromemantines. They basically combine nitroglycerine, an approved drug and memantine, an approved drug, and combined them in a unique way.

Now, I can't tell you that drug works yet, it works in animal models, hopefully it will be safe because it combines, again 2 safe drugs, another repurposing as I mentioned to you earlier. This saves 99% of failures of drugs. If you start a new drug in the brain, almost all of them, 99%, it's been estimated, will fail because of safety or clinical tolerability. We're trying to get around that by repurposing and kind of trying to be clever in combining old drugs that we think get into the brain, and can work in the brain.

Dr. Snyder: Right. So kind of repurposing old drugs, finding new drugs.

"Disease in a Dish"

When we talk about finding new drugs and new approaches, one of the areas that obviously our institute is very strong in and that is getting a lot of attention is this notion of "disease in a dish." Can that kind of approach be applicable to Alzheimer's disease? How is it that you would love to use that? Maybe you could describe a little bit of what that means and how you think you might use it for these kinds of diseases.

Dr. Lipton: Well, not only am I glad that you bought that up but now I get to be the host instead of Evan, who is one of the pioneers for disease in a dish.

So disease in a dish starts with an induced pluripotent stem cell. We take a piece of your skin, and, as Yamanaka and others initially in Japan,[6] and many other groups, have done, including yours and mine,[7,8] we then reprogram those stem cells to become stem cells and then we coach them to become the cell of interest, in this case a nerve cell in your cortex or hippocampus, the areas of the brain that are affected in Alzheimer disease.

The beauty of this is we can do an experiment on human cells from a single human patient in a dish and see if our drugs can protect those synapses. This will speed up research. It doesn't mean we don't do the animal trials, we need to do that. It doesn't mean we don't do the human trials, we need to do that. But it will hopefully help us in 2 ways. We'll kill drugs that don't work, so we won't spend needless hours and millions of dollars or billions of dollars on them, and also it will help us more rapidly screen drugs that we can look at with disease in a dish, and go into our animal models.

The other beauty of this is it will eventually tie in to genomic medicine. We'll be able to take your skin cells, and look to see if this drug affects your cells, and everyone's different. Even if they have Alzheimer disease, it's rare that a single gene causes Alzheimer disease. It's a range of genes that might make you more susceptible and then perhaps there's some environmental influence or something else that triggers it. But by being able to do this kind of personalized medicine in a dish, I think medicine will undergo a revolution in the coming years.

Dr. Snyder: Right. So basically what you're saying is that there's 2 ways that one can use this. You can actually take cells from a real Alzheimer patient and understand why things are going wrong and try to find a drug that can change that pathology, or you could take normal cells and assault it with all kinds of pathological stressors and see how that changes a normal cell into being diseased, and also try to find drugs to protect that.

Dr. Lipton: And, as you know, we can also do both. You can take a cell from a patient with the disease, recreate that disease in a dish, put on stressors -- pesticides, herbicides, fungicides, something from the environment -- and see if that speeds up the disease in a dish, and then try to correlate with epidemiology that might be factor causing the disease.

So I think there's a whole range of possibilities that are opening up with these disease-in-a-dish models, In addition to screening for drugs -- we have one of the biggest screening facilities here, probably the largest outside of a biopharmaceutical company, and we'll be able to screen for drugs using this technology as well.

Looking Ahead

Dr. Snyder: So as we wrap up, what do you think as a practicing neurologist, as well as a researcher at the forefront of this area, that clinicians can look forward to in the coming years -- maybe in the next few years and then maybe in the next decade.

Dr. Lipton: Well, I think a series of new drugs will come out. The key is that the drugs are clinically tolerated. That's been the big problem as we develop drugs, or maybe a cocktail of drugs that we need. It's very hard now to go to the FDA and test a series of drugs, although, as you know, in cancer, it's a series of drugs that works. We have to test one drug at a time, which takes a long time. The average drug takes about 15 years to develop. I think by repurposing drugs, like we've started, we can cut 5 or 10 years off of that. So I'm very hopeful that this is going to proceed in a rapid fashion.

Dr. Snyder: I think you're correct, combine therapies, we would never treat cancer nowadays with just 1 approach. We would never treat AIDS nowadays with 1 approach, and you're probably correct that Alzheimer disease and many neurodegenerative conditions are going to need combinations of approaches, hitting all of the aspects of this very complex pathology.

Dr. Lipton: In fact, right now, the best therapy, although again only symptomatic, is combining a cholinesterase inhibitor to increase acetylcholine with memantine, particularly in moderate to severe Alzheimer disease. That's the best we can do right now.

Dr. Snyder: That was really an interesting topic and a terrific discussion. Thanks for participating in the programs, Stuart.

Dr. Lipton: And that's for having me, Evan.

Dr. Snyder: And we both like to thank you for joining us today. I hope you'll join us for additional programs in the Developments to Watch series on Medscape.


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