Overcoming Bottlenecks in Drug Discovery

Ottavio Arancio, Professor, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, speaks to Pharma IQ, about the goals of his current research, how the landscape for Alzheimer's disease drug discovery has changed in recent years and how novel PDE5 Inhibitors can be used as a therapeutic tool against Alzheimer's disease. Arancio also shares his thoughts on the future of memory research in drug discovery. To listen to the full interview go to Alzheimer's Disease Drug Discovery and the Aging Brain.

Pharma IQ: Could you tell us a bit about the current goals of your research?

O Arancio: The goal of my research is to try to tackle the problem of Alzheimer’s disease at what we call the downstream level of a protein that’s called Beta-amyloid. To make it clearer to people, this protein called Beta-amyloid and it is a protein which accumulates in the brain of people with Alzheimer’s disease. This protein we know is toxic because it affects the communication between cells in the brain, especially in parts of the brain that are very important to learning and memory, and by affecting the connection of these cells in the brain, then, indeed, we know it affects memory.

So the strategy we are using is to try to counteract the negative effect of this protein, Beta-amyloid, on the synaptic function. Instead of using a strategy that most of the people use, which would be to try to reduce the level of this protein, we assume that we know because of other studies that we have performed in my laboratory, we know that the protein, besides being toxic, is also a function for the normal activity of cells, and we know that it is necessary for learning and memory. Therefore if one uses the classical approach that most of the people use that is to reduce the level of this Beta-amyloid, there is the potential to have a negative effect. Instead of ameliorating memory, one could reduce memory. So instead of reducing the levels of this protein, Beta-amyloid, we just leave the Beta-amyloid levels the way in which they are, and instead we try to counteract the negative effect by acting on the targets in the mechanisms that are affected by Beta-amyloid.

In particular at the moment we are acting on two mechanisms. One of them is a mechanism that is important for reading chromatin. Chromatin is where the DNA is, and in order for memory to occur and normal synaptic transmission to occur, it is important this chromatin is opened and read, and then the protein is synthesised. It’s something that involves a mechanism that we call the term AP genetic, and so with one mechanism we are trying to improve the AP genetic mechanisms that are important for learning and memory. We are trying to push this mechanism just to counteract the memory loss.

In another type of molecules or drugs that we are testing in my laboratory, instead we are interacting with cascades of molecular events occurring in the brain that are important for learning and memory, in the heart down regulated by Beta-amyloid. I'm referring to a cascade that bears the name of Nitric Oxide Cascade, by the name of this gas, which involves the production of a molecule called Sigma GMP, and what we do is to inhibit an enzyme that destroys the Sigma GMP, and therefore, by deepening this enzyme we can increase the level of Sigma GMP and help a good connection between cells and good memory.

It’s the kinds of drugs that are called phosphodiesterase five inhibitor, or PD5 inhibitors, to make things easier. While the other one was called heart activator, this stands for Eastern Ascetin Tranferase Activators.

Pharma IQ: Is Alzheimer’s disease in the genes?

O Arancio:The answer is a little bit complex. To give the appropriate correct answer, I have to say that less than 5% of the people affected by Alzheimer’s disease have it because of mutation in the genes. A specific mutation of protein gives the disease. The remaining 95% it's not possible to find a particular mutation of the protein to cause the disease. So that there are also genes that could enhance the risk for having it, the Alzheimer’s disease, although it's not mathematics, that if one has these genes, then they should have Alzheimer's disease, or if one doesn’t have those genes, does not have Alzheimer's. Most likely in this 95% of the cases it’s not strictly speaking genetic. It’s more there is some background that's other. But we should also be aware of the fact that at the age of 85 one person out of two has this disease. At the age of 80 it’s one out of three. So if we live long enough to reach this age, the chance to get the disease is very high. So the biggest risk factor for this disease is aging, which is part of life.

Pharma IQ: How do you feel the landscape for Alzheimer's disease drug discovery has changed in recent years?

O Arancio: What has happened in the field is that there has been a big, big effort to try to tackle levels of Beta-amyloid, and nowadays to act on Tau, which is another protein that is also involved, or modified in this disease. Unfortunately the attempts to use Beta-amyloid so far, or to act on things connected with Beta-amyloid so far have failed, so I can foresee and I hope there will be even more than what there is, unfortunately I can foresee that mainly all my colleagues are asking themselves the question, is there a possibility to tackle the disease behind Beta-amyloid, or behind this protein like Tau.

So I see that the failure in getting successful cures for the disease is causing many scientists to ask that question of what is behind that, and my lab is on the forefront of these people. Indeed, what I just said before about our strategies, our tools, do reflect exactly this unfortunate failure to find this therapy.

With the belief now that if one tackled the disease instead of when it is a mid stage of the disease, at earlier stages, there is more chance to be successful. I agree partially with these things. I do believe that what the field needs, obviously the earlier the better, but we also need to change strategies, and instead of acting directly on this Beta-amyloid, we should find alternative strategies, and indeed the one we are using I think is a valuable one.

Pharma IQ: How can novel PDE5 inhibitors be used as a therapeutic tool against Alzheimer's disease?

O Arancio: PDE5 inhibitors increase the levels of this molecule, which is called Sigma GMP, and this molecule is down regulated, so there is less of it in people affected, or following this elevation of this protein, Beta-amyloid, and we know that this protein is important to be in a certain amount, in high amount, in people during process of memory, and therefore, with our strategy, by using both PDE5 inhibitors, we can elevate the level of the Sigma GMP, which then in turn stimulates another molecule, an enzyme, which is good because it activates another molecule, called CREB, which is important for transcribing genes, and genes that are important for normal communication within cells, and memory as well.

Pharma IQ: How do you feel drug discovery can become more efficient?

O Arancio: This is very, very important question and a very tricky question to even answer. I think that if I had to give a rather philosophical answer, if we are more objective and less bound to our beliefs, etc, and more looking at what is the reality of our experiments, and the results we get from our experiments, instead of sometimes continuing hitting our heads on the wall, that's, in general, just a philosophical answer to your question.
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I think that a way to enhance the yield of the success would be to establish clear criteria of how to paste, for instance, a small molecule, and go for it. Criteria; do have a path to the drug discovery that not only includes assessment of the molecules are doing. Normally you test the activity of this molecule, and then you check, obviously, when the molecule for a brain disease like Alzheimer's disease goes to the brain, whether it is long enough into the brain, whether it is toxic. Obviously it should not be toxic, to be used, but also if we also give great value to also testing memory in the animal models of the disease of various kinds.

If one follows all these rules, my opinion is we should be able to have more chance of success.

There is also, in the case of Alzheimer's disease, a big problem related to the high cost of testing drugs in this disease, which is very subtle, is low, and hard to measure, in the fact because it's slow it takes many years, and therefore it costs a lot of money to test this disease.

And I know, and I agree also with strategies that some of our even big pharmas in some cases have taken just to try to assess the drugs, the small molecules, for instance in diseases that are very close to Alzheimer's disease, but they are faster, for example, Alzheimer's disease versus Huntington’s Disease, or other diseases like this.

If diseases have points in common with Alzheimer’s disease, trying to use these other diseases to test drugs, just to reduce costs, because obviously you can easily understand if you test a drug costs $1 billion, you have only limited, you have less chance to test one drug. Essentially the more things you test, the better it is. You need money for doing things. So if you can reduce the cost of what you're doing, one provision could be that one. That would help a lot.

So I would say less prejudices from us as scientists, a little bit more objectivity. Not that there is not; we are all very serious about our work, but there is always room for improvement, as well as find alternative strategies to reduce cost of doing the research.

And yes, there is obviously the harder thing that resources to do this should be increased. We need more money for research. We have a big problem here in front of us, which threatens our health systems, and it’s not that the cure will be found in one day. So we should invest now, to avoid going bankrupt tomorrow.

Pharma IQ: How can academia and industry work closer together to maximise memory research?

O Arancio:I think the best way would be, and I really see it, to have an exchange of information between the two worlds, which, in the past were quite apart, but my impression is that the two worlds, in the last ten, 15 years, are coming closer and closer. I've seen, because I come, again, from the pure research and the academia, etc, and during these ten, 15 years I have been able to understand more, personally, and like me, many other of my colleagues, there is a big push for doing what's called translational research in academia, and a lot would first would start by my age, but not only, and there is a big demand for people to find drugs, to find therapies, and therefore the two worlds are getting closer, in the sense that there’s much more communication.

Obviously there's always, even for this, room for improvement. Probably there should be less prejudices from both sides. What are changes on the other side, to understand that knowledge, what has changed on the other side?

Another thing I would say is to give also room to new people, to young people with new ideas, to cure and solve diseases. This might be more related to your previous questions, but the two, academia and industry, I think the same problem: if you can find a system to pay more attention to the ideas of young people, instead of the usual old people, perhaps we can find a solution that nobody would have found. New ideas and things that I think the field needs.

Pharma IQ: What do you think the drug discovery landscape is going to look like in the next five to ten years? Are there any particular scientific areas or technologies that you are personally following?

O Arancio:Yes, I personally, with my laboratory, as I said, I'm following targets at the downstream level of Beta-amyloid, and therefore I'm following those two carriers, making a small molecule called heart activators, and the other one, PDE5 inhibitors. Those are the two classes of molecules that we are developing. Within the context of this idea of acting at the downstream level of Beta-amyloid. That's what we're going.

There is also another thing that I think would be very important. A big question that I think we as scientists should emphasise more, and think thoroughly, etc, which is how does the disease start? How come that a molecule, which is toxic, but before being toxic performs a normal function? How come that the molecule, which is in low amount in the brain of people, of normal, healthy people, gets out of control and accumulates in high amount, and therefore it becomes toxic?

It's just to think about the question, how does this start? This is a question that we should pay more attention to, because perhaps in this case it will be before Beta-amyloid. What makes the Beta-amyloid to go up or down? So acting at the upstream level of Beta-amyloid; that would be a big question of finding target that regulates the level of Beta-amyloid and it causes this regulation on the level of Beta-amyloid. That will be a very great question to answer, and if we get a good answer, it will give a very interesting result, and useful to us, for the disease.

You understand that really we need to do a lot of basic work, to understand the real origin of the disease, which we don’t know yet, in most of the people. I don’t mean the less than 5% that, when there is a mutation, and then there is the risk for sure. I mean, the 95 and a little bit more percent, where there is not a clear genetic cause for the disease.

Pharma IQ: I understand you're going to be speaking at IQPC’s Joint Discovery Conference, which is taking place 24^th – 26^th October in Boston. For anyone interested in attending the event, what will be your key take home message?

O Arancio: The key take home message will be that there is hope to ameliorate the quality of life with people with Alzheimer’s disease. If we invest innovatively in science, on things that we know that effectively they can affect ultimate mechanism in this disease, such as, for instance, these factors are the downstream level of Beta-amyloid, one. And the second take home message is that if I would be able to convince people investing in research to try to understand the real origins of the disease, it will be a fantastic thing that could happen. 

Interview conducted by Andrea Charles.

IQPC

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