Attacking Alzheimer’s With Antibodies, Hormones
Researchers are attempting to treat Alzheimer’s disease with antibodies, hormones and gene therapy. But will any lead to a cure? Ronald Petersen, director of the Mayo Alzheimer’s Disease Research Center, talks about the latest research, and whether there might someday be a vaccine to protect the aging brain.
Transcript
IRA FLATOW, HOST:
This is SCIENCE FRIDAY, I’m Ira Flatow. Earlier this week, yet another potential cure for Alzheimer’s failed. Pfizer called off additional studies of its intravenous drug bapineuzumab, an antibody designed to seek and destroy plaques that build up in the brains of people with Alzheimer’s.
The thinking was that if you clear the plaques, maybe the dementia will improve or go away. Unfortunately, the drug did not seem to do that. But it’s not the only possibility. Researchers are testing other types of antibodies. They’re testing hormones. They’re trying gene therapy. What are the chances that these approaches will pan out? Might we see an Alzheimer’s vaccine someday? That’s what we’re going to be talking about, a status check on Alzheimer’s research.
Our number is 1-800-989-8255. You can tweet us @scifri, and you can also go to our website at sciencefriday.com.
Dr. Ronald Petersen is director of the Mayo Alzheimer’s Disease Research Center at the Mayo Clinic in Rochester, Minnesota. Welcome to SCIENCE FRIDAY, Dr. Petersen.
RONALD PETERSEN: Thanks very much, Ira.
FLATOW: First give us a little inside baseball on what happened with the Pfizer drug. Did it not clear the plaques? Do we know? Do we know why it failed?
PETERSEN: Well, it was a preliminary report regarding the clinical findings, meaning that the memory, the functional changes in these patients with the mild to moderate state of the dementia of Alzheimer’s disease, the clinical features did not improve.
What we don’t know yet, they haven’t announced yet, is whether the drug actually had an impact on the underlying biological process. So there was no clinical improvement, but we’re still waiting for data on the biological signal. Did the antibody do what it was supposed to do in the brain?
FLATOW: And it was supposed to clear out the amyloid plaques, correct?
PETERSEN: That’s right, I mean, amyloid is thought to be a major player in the disease process. So amyloid is a normal protein in the brain, even though we don’t exactly understand what it does. It is a normal protein, but when it gets processed abnormally, for a variety of reasons, then it clumps in the brain, forms this sticky insoluble substance that then destroys the nerve cells around it.
So if that happens in the memory part of the brain, the person then becomes forgetful. So this antibody was meant to get in there and detach that amyloid and metabolize it and get it out of the brain.
FLATOW: You know, what happens? I imagine for any drug to reach the stage of human trials, it has to show that it works in a Petri dish and then in animals.
PETERSEN: Sure.
FLATOW: Well, what happens between then and the human trials? Why the disconnect so often?
PETERSEN: Well, you know, a little over 10 years ago, there were some very exciting data presented showing that in transgenic mice – so these are mice now that are given a human gene to produce the amyloid-like substance in the brain, much like you see in Alzheimer’s disease – that when these mice, who again are genetically programmed to develop this amyloid in the brain, when they were immunized one month after birth, they did not develop the amyloid proteins by the genetic predisposition.
So this was very exciting that in fact we may be able to treat Alzheimer’s disease with a vaccine. Well, moving that from the mouse to the human is not trivial. And of course this isn’t necessarily a model of Alzheimer’s disease, it’s a model of amyloid doses, so to speak, in the brain.
Nevertheless, this was felt to be pretty exciting, and so a human trial was designed shortly after that. It ran for a few months and then had to be terminated because there were some side effects, inflammatory responses in the brain, in about five percent of the subjects in that study. So it was stopped.
But nevertheless, people went back to the drawing board to design either better vaccines or antibodies, as we saw the bapineuzumab trial. So the animal data are very compelling. The rationale is there, but it’s not an easy transition to go into the human.
FLATOW: There’s always that problem of will it work, and of course as you say this is not a perfect model for Alzheimer’s, and you would not give this as a test to young people, as you did to young rats in a laboratory.
PETERSEN: Right. I mean, this is the conundrum in the field of Alzheimer’s disease research right now. These strategies that are meant to modify this amyloid protein, either remove it or stop it from being deposited in the first place, make good sense. But we’re restricted, to a certain extent, to treating people or running studies in people with, say, mild dementia of Alzheimer’s disease.
It may be too late. It may be like giving a statin to somebody after the heart attack. Now, we do that, clinically, but in fact we maybe should have given that statin years, if not decades, earlier. So the conundrum in the Alzheimer’s field is that while these strategies are very well-reasoned, and we have animal models that indicate they may work. We would really need to start much earlier in the disease process, maybe even at the mild cognitive impairment stage, which is before dementia, or preferably in the asymptomatic stage, where people are really clinically normal but have the biological predisposition to develop it.
That may be where you want to intervene, but that’s a tricky hurdle. It’s very expensive and maybe a little risky to do that.
FLATOW: Yeah because we don’t know what the long-term effects, because you’re giving it to younger people.
PETERSEN: Exactly. I mean, when you’re talking about giving it to, say, a 30- or 40-year-old for the rest of his or her life, it really becomes problematical. Now here’s where a vaccine, an active vaccine rather than a passive antibody, might be preferable. But again, that is proof of concept there, and there’s a lot of safety that needs to be demonstrated before you go into humans.
FLATOW: Let me explore that a bit longer. How would you make an active vaccine? What would it be made out of, and how would you give it?
PETERSEN: A piece of synthetic amyloid protein. So you take and inject that. Much like with the polio vaccine that everybody’s well familiar with, this is a piece of an inactivated polio virus. You inject that into the person, and the person’s body then generates antibodies to protect you against that particular virus.
So now take that concept and go to Alzheimer’s disease, you take a piece of this synthetic amyloid protein, inject it into the person, the person’s own body then generates antibodies against that amyloid protein and therefore hopefully protecting you against Alzheimer’s disease.
FLATOW: But as you say, if amyloid is a normal part of your brain, it’s there anyhow, only when something goes wrong does it cause Alzheimer’s. Why would – you know, why would injecting your piece of your own body create an immune effect?
PETERSEN: Well, what you would have to do is inject the abnormal protein, so the mis-processed protein itself so that you would develop immunity against the abnormal form of the amyloid protein, not the normal form. But again, the devil’s in the details here, is how you do that, make sure there’s no cross-reaction against something else.
FLATOW: Is that being tested anywhere, or tried out?
PETERSEN: There are, there are trials underway right now of an active vaccine, as well. So again, the scientists have gone back to the drawing board and said gee, when we did that study back in the early 2000s with the active vaccine, what went wrong, what could have caused this inflammatory response. So they’ve modified the protein now and have been able to develop one that they hope will in fact generate the immune response without the side effects.
FLATOW: Why doesn’t Alzheimer’s kick in earlier in life for those who are genetically predisposed to it? Why does it wait until you’re in your 70s or 80s?
PETERSEN: That’s a good question, Ira. I mean, it’s a million-dollar question as to what are the other aging factors that have to kick in, and basically we don’t know the answer to that. But one issue might be, for example, that our immune systems diminish in their effectiveness and ability to perform their work as we age.
So a challenge in using an active vaccine in an older person is that the older person may not be able to generate an antibody response. So if, say, Alzheimer’s disease were partly immunologically driven, it may only manifest itself when the person’s aging immune system starts to fail or diminish its effectiveness. Then this blossoms. I’m not saying that’s the answer, but it’s that type of thing.
There are other aging factors. There’s oxidative stress, inflammatory reasons, a variety of factors that may kick in with aging that allow the predisposition to express itself.
FLATOW: You know, there is research with scientists looking at gene therapy, modifying neurons in a dish that seem to work in the dish. Getting it out of that dish seems to be the problem. It almost seems like we’re right there, almost.
PETERSEN: You’re absolutely right. I mean, last month in Vancouver was the Alzheimer’s Association International Conference, and it was there, and then over 4,000 to almost 5,000 people, researchers, were there. And I think the field is poised. It really is poised to make that next step so that we have a variety of therapies, not only anti-amyloid therapies but a variety of other therapies that may be effective, but we just can’t get there.
Now I hate to get on a bandwagon here, but part of this is funding. I mean, it really does take a significant amount of funding to push this research to the next step. When you start talking about these drug trials like the Pfizer J&J one, you’re talking $100 million. So it’s major investments.
And so to develop these compounds really does take an investment, but with the cost of the disease and the projected cost of the disease as America and other societies age, it just makes sense. We have to do it now.
FLATOW: You also served as an advisor for the National Alzheimer’s Project Act. What is that?
PETERSEN: Well, the National Alzheimer’s Project Act was signed into law by the president in January of 2011, and that law essentially charged the secretary of health and human services, Kathleen Sebelius, to develop a national plan for Alzheimer’s disease, this is the first one in this country. And I had the honor of chairing the advisory committee for the development of the plan.
And the plan was developed and released in May of this year and basically has five goals. One’s a research goal, how we can effectively treat, maybe prevent Alzheimer’s disease. Another goal had to do with making the diagnosis earlier, being better diagnosticians with regard to how the diagnosis is made.
A third goal had to do with caring for caregivers, the people who really take the brunt of this disease and need their support. The fourth was awareness and education of the general population. And the fifth goal was how are we going to measure whether we’re making progress or not, what are the metrics out there.
So all of this has been put out now, and it’s a rather ambitious plan. It’s gone to the secretary, it’s gone to Congress, and now as we were just discussing, it really is on Congress’ table. They passed it. Now they have to act on doing something about this to make it a reality.
FLATOW: Dr. Petersen, thank you very much for taking time to talk with us.
PETERSEN: My pleasure. Thank you, Ira.
FLATOW: Ronald Petersen, director of the Mayo Alzheimer’s Disease Research Center. You can go to our website, we have some paintings done by Alzheimer’s as part of the Artists for Alzheimer’s Program. We’ll be right back after this break. I’m Ira Flatow, this is SCIENCE FRIDAY from NPR.
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