Jerold Chun, MD, PhD, Professor and Senior Vice-President at the Sanford Burnham Prebys Medical Discovery Institute talks about how HIV drugs can help Alzheimer’s patients.
Interview conducted by Ivanhoe Broadcast News in January 2019.
As common a disease is, a condition is – there’s not a ton of research that has actually panned out yet for identification and treatment.
Jerold: The research that we’ve been involved with is at a basic level, but it has implications that could provide near-term therapeutics. The basic observation is that within the cells of our brain, the blueprint, the DNA, can actually change. That’s distinct from what you’re taught in school, where the blueprint is immutable in every cell of your body. But within the brain, that’s not the case. There’s actually enormous numbers or amounts of variation that can be found. And in this case, it’s a variation of an actual gene. The gene is what gives rise to proteins within your body. And in this case, this gene, a very famous one in the Alzheimer’s Disease world, called APP or amyloid precursor protein, gets turned from its normal, say, two copies, or in the case of Down syndrome, three copies, to actually producing thousands and thousands of distinct forms that enter this DNA blueprint of individual neurons. We believe that is a process which hasn’t been recognized before that could then give rise over time to the most common form of Alzheimer’s disease.
Is that why it’s been so hard to kind of get a grasp on treatment and identification?
Jerold: That’s in part. Also, it’s the realization that we are, what’s called, a genomic mosaic, and that means that there’s this individual variation of DNA from cell to cell. That mosaicism means that if you just took the whole kit and caboodle and looked at it, you wouldn’t see it because it would be mixed up with things that were not affected. You have to get down there and look at just a few cells or single cells to be able to detect it.
What do you do with this information now?
Jerold: There’s two basic areas that need to be explored. One is the continued science about how these form, the actual functions at a cellular level. That all needs to be sorted out, including the biosynthetic machinery, that falls into the category of basic science. But then therapeutically, these new variants raise the possibility that we can get at a completely new set of therapeutic targets that could be accessed by looking at these changed genes, including the enzymes, for example, that give rise to them and that might be targeted themselves. There is some very interesting proof-of-concept data out there from the HIV patient community that receives something called a “reverse transcriptase inhibitor.” It turns out that one of the enzymes that actually produces this recombination process is a reverse transcriptase. You can inhibit these with medicines, and in fact, that’s what keeps, in part, the HIV-infected patient community alive. It’s now at the point where many of these patients are old enough to get Alzheimer’s disease. That number is actually quite large, something like close to 120,000 people, based on the Centers for Disease Control. That would suggest that there should be thousands – anywhere from 3 to 10 percent of these folks – with Alzheimer’s disease. So how many do you think have been actually recorded with Alzheimer’s disease in that population? There’s been only one so far. That was just a couple of years ago. It’s looking like there’s some type of a signal there. Now, this was not a controlled clinical trial. This is simply looking at the data in the literature. What we need to do now is to actually run clinical trials. But there’s also the option of what’s called off label prescriptions because these are already FDA approved agents. So rather than being a completely new type of chemical compound that might have horrible adverse events – side effects – this actually has some defined properties that might allow someone, were they to discuss that with a physician and decide it’s the right thing to do, that they could embark on that kind of therapy.
Would they be tested for the DNA for the…
Jerold: At this point, we don’t have tests for that so this would be Alzheimer’s disease.
So simultaneously, while you and your lab and your research partners are working on finding out, doing trials, if they can get it off label.
Jerold: That’s correct. There’s something that falls into a category of compassionate use. Or I think the government now has something called right to try, so this concept is important, in that if one were to wait until any numbers of hopefully successful medicines make it out of these clinical trials, and there are many, many trials ongoing, it’ll still take a long time, and that may be too late for a lot of people.
So the HIV drugs, what do they do? Do they reverse? Do they stop? Do they prevent? What do they do?
Jerold: We don’t know the complete answer to that. What we think is that they would at least delay and potentially prevent the development of more severe Alzheimer’s disease. Once it is full blown, fully manifested, we’re not sure. That might be too late. We just don’t know at this point. There are a number of different aspects of disease related to this therapeutic that have to be determined. That requires controlled clinical trials.
How close do you think you are to trial?
Jerold: I’d say within a year or so. I mean, I’m optimistic that we can get enough support and input from the community, clinical community. We’re actively discussing these options right now.
What kind of side effects do the drugs have on patients with HIV?
Jerold: It is a vast range. There’s something on the order of 26 different medicines that fall into this category. And they have different properties, different side effect profiles. But overall, they’re fairly well tolerated. And in some cases, have been in patients for decades without really severe adverse events. So, that’s promising.
The gene shuffling, this could change the course of how Alzheimer’s research goes, right?
Jerold: Well, it’s possible. We certainly need to know more about it. That’s an active area of research in our lab, and we’d love to work with people to make that happen. That’s a really important point. There simply are not any approved medicines out there to really be; we’d call them disease-modifying therapies. There simply aren’t any. That puts the current set of observations into sort of a different category, since now there could be. It doesn’t say this will work, and it may not work or may only work in a subpopulation. We just don’t know that. But at least there is a way to test this in a realistic way because it’s already an approved medicine.
What else haven’t I asked you about your research that you think is important to get in this story?
Jerold: This also has bearing on fundamental aspects of how the brain functions. One of the things that we know is, over time, we learn and remember, and then things get disrupted, of course, in Alzheimer’s disease but other forms of dementia as well. This mechanism could extend beyond Alzheimer’s disease and actually be relevant to a number of other types of brain disorders. It may be behind some aspects of what we call learning and memory. What happens is that a form of a gene within our bodies, we have two copies of the gene, one for mom, one for dad, and then the ideas have been that that is immutable. We know that some of these, at least in some cases, as APP, some of these genes can form all of these other forms. Well, if you can encode in that blueprint different combinations of these, then you’ll get a different output in that cell. So basically, you’re rewriting – in real time, as you’re living, learning, aging – that blueprint that allows you, we think, to alter things like your functionality or behavior or maybe your mood, cognition. These are all things that are possible to discuss in this framework now, and we’d love to do that.
The regenerating of all these copies of the gene, does it happen in everybody with Alzheimer’s, or do you not know yet?
Jerold: Well, we think it happens normally, and then it gets dysregulated in Alzheimer’s. It’s a great question about; does it happen in all forms of Alzheimer’s? That’s something we’re actively looking at right now.
What are some of the signs of Alzheimer’s?
Jerold: Changes in cognition, changes in memory. Changes in cognition, changes in memory, and especially in shorter term memory, changes in personality. These can all fit into Alzheimer’s early presentation.
How does memory loss first appear for – take place? Which I think you might’ve just answered.
Jerold: Memory loss can manifest in a number of different ways. Things that you and I experience as well – keys, etcetera. But it can then be more, I think, severe. You walk out the door and don’t know where you are. That’s the type of thing that can be encountered. And when it starts to happen on a more regular basis, then that’s a sign that something is going on.
What are some of the most common memories forgotten? Like long term, short term?
Jerold: Typically, they’re shorter term. The long term seemed to be sustained for a much longer period of time, before they too can be lost in the most severe cases. It seems to be shorter term memories that get lost.
Could it be possible to one day to reverse memory loss in patients?
Jerold: Memory loss, I think, would be more challenging to reverse. It’s possible you could reboot, if you want to use a computer terminology, the brain in some way that had memories and get them back in there. But that’s a sort of a different proposition.
Is there anything families can do to help their loved ones remember things, slow down progression?
Jerold: Well, from the memory standpoint, there are efforts that are being done to provide an environment that is familiar to that patient. Putting them into a setting where they can relate to things that they had known from a previous part of their life. In fact, there are some efforts to put communities together where patients can actually be in, say, a world that was 20, 30 years ago and feel more comfortable at least and, in some ways, interact better in that environment. I think the support of these patients is absolutely critical. Hopefully, they’ll be therapeutics that can help that. But in the meantime, standard types of things, protect their safety, make sure they don’t go wandering off and get hurt. Make sure that they’re not taking any types of medications that might actually put them at risk for other events. And then of course, a full workup to make sure that that’s actually what the disease process is, and it’s not something else.
END OF INTERVIEW
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